Fused bicyclic heteroaromatic derivatives as modulators of TNF activity

ABSTRACT

A series of substituted heteroaromatic compounds containing two fused six-membered rings, tivity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

This application is the US national phase under 35 U.S.C. §371 ofinternational application PCT/EP2014/076877, filed Dec. 8, 2014, whichclaims priority to GB application 1321752.6, filed Dec. 9, 2013, and GB1409244.9, filed May 23, 2014.

The present invention relates to a class of fused bicyclicheteroaromatic derivatives, and to their use in therapy. Moreparticularly, this invention is concerned with pharmacologically activesubstituted heteroaromatic compounds containing two fused six-memberedrings. These compounds are modulators of the signalling of TNFα, and areaccordingly of benefit as pharmaceutical agents, especially in thetreatment of adverse inflammatory and autoimmune disorders, neurologicaland neurodegenerative disorders, pain and nociceptive disorders,cardiovascular disorders, metabolic disorders, ocular disorders, andoncological disorders.

TNFα is the prototypical member of the Tumour Necrosis Factor (TNF)superfamily of proteins that share a primary function of regulating cellsurvival and cell death. One structural feature common to all knownmembers of the TNF superfamily is the formation of trimeric complexesthat bind to, and activate, specific TNF superfamily receptors. By wayof example, TNFα exists in soluble and transmembrane forms and signalsthrough two receptors, known as TNFR1 and TNFR2, with distinctfunctional endpoints.

Various products capable of modulating TNFα activity are alreadycommercially available. All are approved for the treatment ofinflammatory and autoimmune disorders such as rheumatoid arthritis andCrohn's disease. All currently approved products are macromolecular andact by inhibiting the binding of human TNFα to its receptor. Typicalmacromolecular TNFα inhibitors include anti-TNFα antibodies; and solubleTNFα receptor fusion proteins. Examples of commercially availableanti-TNFα antibodies include fully human antibodies such as adalimumab(Humira®) and golimumab (Simponi®), chimeric antibodies such asinfliximab (Remicade®), and pegylated Fab′ fragments such ascertolizumab pegol (Cimzia®). An example of a commercially availablesoluble TNFα receptor fusion protein is etanercept (Enbrel®).

TNF superfamily members, including TNFα itself, are implicated in avariety of physiological and pathological functions that are believed toplay a part in a range of conditions of significant medical importance(see, for example, M. G. Tansey & D. E. Szymkowski, Drug DiscoveryToday, 2009, 14, 1082-1088; and F. S. Carneiro et al., J. SexualMedicine, 2010, 7, 3823-3834).

The compounds in accordance with the present invention, being potentmodulators of human TNFα activity, are therefore beneficial in thetreatment and/or prevention of various human ailments. These includeautoimmune and inflammatory disorders; neurological andneurodegenerative disorders; pain and nociceptive disorders;cardiovascular disorders; metabolic disorders; ocular disorders; andoncological disorders.

In addition, the compounds in accordance with the present invention maybe beneficial as pharmacological standards for use in the development ofnew biological tests and in the search for new pharmacological agents.Thus, in one embodiment, the compounds of this invention may be usefulas radioligands in assays for detecting pharmacologically activecompounds. In an alternative embodiment, certain compounds of thisinvention may be useful for coupling to a fluorophore to providefluorescent conjugates that can be utilised in assays (e.g. afluorescence polarisation assay) for detecting pharmacologically activecompounds.

Co-pending international patent applications WO 2013/186229 (published19 Dec. 2013), WO 2014/009295 (published 16 Jan. 2014) and WO2014/009296 (also published 16 Jan. 2014) describe fused imidazolederivatives which are modulators of human TNFα activity.

None of the prior art available to date, however, discloses or suggeststhe precise structural class of fused bicyclic heteroaromaticderivatives as provided by the present invention.

The compounds in accordance with the present invention potently inhibitthe binding of a fluorescence conjugate to TNFα when tested in thefluorescence polarisation assay described herein. Indeed, when tested inthat assay, the compounds of the present invention exhibit an IC₅₀ valueof 50 μM or less, generally of 20 μM or less, usually of 5 μM or less,typically of 1 μM or less, suitably of 500 nM or less, ideally of 100 nMor less, and preferably of 20 nM or less (the skilled person willappreciate that a lower IC₅₀ figure denotes a more active compound).

Certain compounds in accordance with the present invention potentlyneutralise the activity of TNFα in a commercially available HEK-293derived reporter cell line known as HEK-Blue™ CD40L. This is a stableHEK-293 transfected cell line expressing SEAP (secreted embryonicalkaline phosphatase) under the control of the IFNβ minimal promoterfused to five NF-κB binding sites. Secretion of SEAP by these cells isstimulated in a concentration-dependent manner by TNFα. When tested inthe HEK-293 bioassay, also referred to herein as the reporter geneassay, certain compounds of the present invention exhibit an IC₅₀ valueof 50 μM or less, generally of 20 μM or less, usually of 5 μM or less,typically of 1 μM or less, suitably of 500 nM or less, ideally of 100 nMor less, and preferably of 20 nM or less (as before, the skilled personwill appreciate that a lower IC₅₀ figure denotes a more activecompound).

The present invention provides a compound of formula (I) or an N-oxidethereof, or a pharmaceutically acceptable salt or solvate thereof, or aglucuronide derivative thereof, or a co-crystal thereof:

wherein

q is zero or 1;

A represents C—R² or N;

B represents C—R³ or N;

D represents C—R⁴ or N;

G represents the residue of a six-membered heteroaromatic ring selectedfrom pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl;

E represents a covalent bond; or E represents —O—, —S—, —S(O)—, —S(O)₂—,—S(O)(NR⁵)— or —N(R⁵)—; or E represents an optionally substitutedstraight or branched C₁₋₄ alkylene chain;

Q represents a covalent bond; or Q represents —O—, —S—, —S(O)—, —S(O)₂—,—S(O)(NR⁶)—, —N(R⁶)—, —C(O)N(R⁶)—, —N(R⁶)C(O)—, —S(O)₂N(R⁶)— or—N(R⁶)S(O)₂—; or Q represents an optionally substituted straight orbranched C₁₋₆ alkylene chain optionally comprising one, two or threeheteroatom-containing linkages independently selected from —O—, —S—,—S(O)—, —S(O)₂—, —S(O)(NR⁶)—, —N(R⁶)—, —C(O)N(R⁶)—, —N(R⁶)C(O)—,—S(O)₂N(R⁶)— and —N(R⁶)S(O)₂—;

Y represents C₃₋₇ cycloalkyl, aryl, C₃₋₇ heterocycloalkyl or heteroaryl,any of which groups may be optionally substituted by one or moresubstituents;

Z represents hydrogen, halogen or trifluoromethyl; or Z represents C₁₋₆alkyl, C₃₋₇ cycloalkyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkenyl or heteroaryl, any of which groups may be optionallysubstituted by one or more substituents; or Z represents —Z¹—Z² or—Z¹—C(O)—Z², either of which moieties may be optionally substituted byone or more substituents;

Z¹ represents a divalent radical derived from an aryl, C₃₋₇heterocycloalkyl or heteroaryl group;

Z² represents aryl, C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl orheteroaryl;

R¹, R², R³ and R⁴ independently represent hydrogen, halogen, cyano,nitro, hydroxy, trifluoromethyl, trifluoromethoxy, —OR^(a), —SR^(a),—SOR^(a), —SO₂R^(a), —SF₅, —NR^(b)R^(c), —NR^(c)COR^(d),—NR^(c)CO₂R^(d), —NHCONR^(b)R^(c), —NR^(c)SO₂R^(e), —N(SO₂R^(e))₂,—NHSO₂NR^(b)R^(c), —COR^(d), —CO₂R^(d), —CONR^(b)R^(c),—CON(OR^(a))R^(b), —SO₂NR^(b)R^(c) or —SO(NR^(b))R^(e); or C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₃₋₇cycloalkyl(C₁₋₆)alkyl, aryl, aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl,C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkenyl, C₄₋₉heterobicycloalkyl, heteroaryl, heteroaryl(C₁₋₆)alkyl,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-,heteroaryl(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl(C₁₋₆)alkyl-heteroaryl-, (C₄₋₇)cycloalkenyl-heteroaryl-,(C₄₋₉)bicycloalkyl-heteroaryl-, (C₃₋₇)heterocycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-hetero aryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents;

R⁵ and R⁶ independently represent hydrogen or C₁₋₆ alkyl;

R^(a) represents C₁₋₆ alkyl, aryl, aryl(C₁₋₆)alkyl, heteroaryl orheteroaryl(C₁₋₆)alkyl, any of which groups may be optionally substitutedby one or more substituents;

R^(b) and R^(c) independently represent hydrogen or trifluoromethyl; orC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, aryl,aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any ofwhich groups may be optionally substituted by one or more substituents;or

R^(b) and R^(c), when taken together with the nitrogen atom to whichthey are both attached, represent azetidin-1-yl, pyrrolidin-1-yl,oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl,isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl,piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl orhomopiperazin-1-yl, any of which groups may be optionally substituted byone or more substituents;

R^(d) represents hydrogen; or C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, C₃₋₇heterocycloalkyl or heteroaryl, any of which groups may be optionallysubstituted by one or more substituents; and

R^(e) represents C₁₋₆ alkyl, aryl or heteroaryl, any of which groups maybe optionally substituted by one or more substituents.

The present invention also provides a compound of formula (I) as definedabove or an N-oxide thereof, or a pharmaceutically acceptable salt orsolvate thereof, or a glucuronide derivative thereof, or a co-crystalthereof, for use in therapy.

The present invention also provides a compound of formula (I) as definedabove or an N-oxide thereof, or a pharmaceutically acceptable salt orsolvate thereof, or a glucuronide derivative thereof, or a co-crystalthereof, for use in the treatment and/or prevention of disorders forwhich the administration of a modulator of TNF a function is indicated.

In another aspect, the present invention provides a compound of formula(I) as defined above or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, or a glucuronide derivative thereof,or a co-crystal thereof, for use in the treatment and/or prevention ofan inflammatory or autoimmune disorder, a neurological orneurodegenerative disorder, pain or a nociceptive disorder, acardiovascular disorder, a metabolic disorder, an ocular disorder, or anoncological disorder.

The present invention also provides a method for the treatment and/orprevention of disorders for which the administration of a modulator ofTNFα function is indicated which comprises administering to a patient inneed of such treatment an effective amount of a compound of formula (I)as defined above or an N-oxide thereof, or a pharmaceutically acceptablesalt or solvate thereof, or a glucuronide derivative thereof, or aco-crystal thereof.

In another aspect, the present invention provides a method for thetreatment and/or prevention of an inflammatory or autoimmune disorder, aneurological or neurodegenerative disorder, pain or a nociceptivedisorder, a cardiovascular disorder, a metabolic disorder, an oculardisorder, or an oncological disorder, which comprises administering to apatient in need of such treatment an effective amount of a compound offormula (I) as defined above or an N-oxide thereof, or apharmaceutically acceptable salt or solvate thereof, or a glucuronidederivative thereof, or a co-crystal thereof.

Where any of the groups in the compounds of formula (I) above is statedto be optionally substituted, this group may be unsubstituted, orsubstituted by one or more substituents. Typically, such groups will beunsubstituted, or substituted by one or two substituents.

For use in medicine, the salts of the compounds of formula (I) will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds of use in the invention or of theirpharmaceutically acceptable salts. Standard principles underlying theselection and preparation of pharmaceutically acceptable salts aredescribed, for example, in Handbook of Pharmaceutical Salts: Properties,Selection and Use, ed. P. H. Stahl & C. G. Wermuth, Wiley-VCH, 2002.Suitable pharmaceutically acceptable salts of the compounds of use inthis invention include acid addition salts which may, for example, beformed by mixing a solution of the compound of use in the invention witha solution of a pharmaceutically acceptable acid such as hydrochloricacid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid,succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid orphosphoric acid. Furthermore, where the compounds of use in theinvention carry an acidic moiety, e.g. carboxy, suitablepharmaceutically acceptable salts thereof may include alkali metalsalts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g.calcium or magnesium salts; ammonium salts; and salts formed withsuitable organic ligands, e.g. quaternary ammonium salts, and megluminesalts.

The present invention includes within its scope solvates of thecompounds of formula (I) above. Such solvates may be formed with commonorganic solvents, e.g. hydrocarbon solvents such as benzene or toluene;chlorinated solvents such as chloroform or dichloromethane; alcoholicsolvents such as methanol, ethanol or isopropanol; ethereal solventssuch as diethyl ether or tetrahydrofuran; or ester solvents such asethyl acetate. Alternatively, the solvates of the compounds of formula(I) may be formed with water, in which case they will be hydrates.

The present invention also includes co-crystals within its scope. Thetechnical term “co-crystal” is used to describe the situation whereneutral molecular components are present within a crystalline compoundin a definite stoichiometric ratio. The preparation of pharmaceuticalco-crystals enables modifications to be made to the crystalline form ofan active pharmaceutical ingredient, which in turn can alter itsphysicochemical properties without compromising its intended biologicalactivity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L.Quere, RSC Publishing, 2012). Typical examples of co-crystal formers,which may be present in the co-crystal alongside the activepharmaceutical ingredient, include L-ascorbic acid, citric acid,glutaric acid, urea and nicotinamide.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,ed. H. Bundgaard, Elsevier, 1985.

Suitable alkyl groups which may be present on the compounds of use inthe invention include straight-chained and branched C₁₋₆ alkyl groups,for example C₁₋₄ alkyl groups. Typical examples include methyl and ethylgroups, and straight-chained or branched propyl, butyl and pentylgroups. Particular alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyland 3-methylbutyl. Derived expressions such as “C₁₋₆ alkoxy”, “C₁₋₆alkylthio”, “C₁₋₆ alkylsulphonyl” and “C₁₋₆ alkylamino” are to beconstrued accordingly.

The expression “C₁₋₄ alkylene chain” refers to a divalent straight orbranched alkylene chain containing 1 to 4 carbon atoms. Typical examplesinclude methylene, ethylene, methylmethylene, ethylmethylene anddimethylmethylene.

Suitable C₂₋₆ alkenyl groups include vinyl and allyl.

Suitable C₂₋₆ alkynyl groups include ethynyl, propargyl and butynyl.

The term “C₃₋₇ cycloalkyl” as used herein refers to monovalent groups of3 to 7 carbon atoms derived from a saturated monocyclic hydrocarbon, andmay comprise benzo-fused analogues thereof. Suitable C₃₋₇ cycloalkylgroups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl,indanyl, cyclohexyl and cycloheptyl.

The term “C₄₋₇ cycloalkenyl” as used herein refers to monovalent groupsof 4 to 7 carbon atoms derived from a partially unsaturated monocyclichydrocarbon. Suitable C₄₋₇ cycloalkenyl groups include cyclobutenyl,cyclopentenyl, cyclohexenyl and cycloheptenyl.

The term “C₄₋₉ bicycloalkyl” as used herein refers to monovalent groupsof 4 to 9 carbon atoms derived from a saturated bicyclic hydrocarbon.Typical bicycloalkyl groups include bicyclo[3.1.0]hexanyl,bicyclo[4.1.0]heptanyl and bicyclo[2.2.2]octanyl.

The term “aryl” as used herein refers to monovalent carbocyclic aromaticgroups derived from a single aromatic ring or multiple condensedaromatic rings. Suitable aryl groups include phenyl and naphthyl,preferably phenyl.

Suitable aryl(C₁₋₆)alkyl groups include benzyl, phenylethyl,phenylpropyl and naphthylmethyl.

The term “C₃₋₇ heterocycloalkyl” as used herein refers to saturatedmonocyclic rings containing 3 to 7 carbon atoms and at least oneheteroatom selected from oxygen, sulphur and nitrogen, and may comprisebenzo-fused analogues thereof. Suitable heterocycloalkyl groups includeoxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzo-furanyl,dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl,oxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl,tetrahydropyranyl, chromanyl, tetrahydro-thiopyranyl, piperidinyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl,hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazinyl, homopiperazinyl,morpholinyl, benzoxazinyl, thiomorpholinyl, azepanyl, oxazepanyl,diazepanyl, thiadiazepanyl and azocanyl.

The term “C₃₋₇ heterocycloalkenyl” as used herein refers tomonounsaturated or polyunsaturated monocyclic rings containing 3 to 7carbon atoms and at least one heteroatom selected from oxygen, sulphurand nitrogen, and may comprise benzo-fused analogues thereof. Suitableheterocycloalkenyl groups include thiazolinyl, isothiazolinyl,imidazolinyl, dihydropyranyl, dihydrothiopyranyl and1,2,3,6-tetrahydropyridinyl.

The term “C₄₋₉ heterobicycloalkyl” as used herein corresponds to C₄₋₉bicycloalkyl wherein one or more of the carbon atoms have been replacedby one or more heteroatoms selected from oxygen, sulphur and nitrogen.Typical heterobicycloalkyl groups include 3-azabicyclo[3.1.0]hexanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.2.0]heptanyl,3-azabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl,3-azabicyclo[4.1.0]-heptanyl, 2-oxabicyclo[2.2.2]octanyl, quinuclidinyl,2-oxa-5-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl,8-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl,3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.2]nonanyl,3-oxa-7-azabicyclo-[3.3.1]nonanyl, 3,7-dioxa-9-azabicyclo[3.3.1]nonanyland 3,9-diazabicyclo[4.2.1]nonanyl.

The term “C₄₋₉ spiroheterocycloalkyl” as used herein refers to saturatedbicyclic ring systems containing 4 to 9 carbon atoms and at least oneheteroatom selected from oxygen, sulphur and nitrogen, in which the tworings are linked by a common atom. Suitable spiroheterocycloalkyl groupsinclude 5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]-heptanyl,2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl,3-oxa-6-azaspiro[3.3]-heptanyl, 6-thia-2-azaspiro[3.3]heptanyl,2-oxa-6-azaspiro[3.4]octanyl, 2-oxa-6-azaspiro-[3.5]nonanyl,7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro[3.5]nonanyl and2,4,8-triazaspiro[4.5]decanyl.

The term “heteroaryl” as used herein refers to monovalent aromaticgroups containing at least 5 atoms derived from a single ring ormultiple condensed rings, wherein one or more carbon atoms have beenreplaced by one or more heteroatoms selected from oxygen, sulphur andnitrogen. Suitable heteroaryl groups include furyl, benzofuryl,dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl,thieno[3,4-b][1,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrrolo[3,4-b]pyridinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl,pyrazolo[3,4-c]pyrimidinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl,oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl,isothiazolyl, imidazolyl, benzimidazolyl, imidazo[2,1-b]thiazolyl,imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, purinyl,imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrazinyl, oxadiazolyl,thiadiazolyl, triazolyl, [1,2,4]triazolo[1,5-a]-pyrimidinyl,benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl,naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl,quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl andchromenyl groups.

The term “halogen” as used herein is intended to include fluorine,chlorine, bromine and iodine atoms, typically fluorine, chlorine orbromine.

Where the compounds of formula (I) have one or more asymmetric centres,they may accordingly exist as enantiomers. Where the compounds of use inthe invention possess two or more asymmetric centres, they mayadditionally exist as diastereomers. The invention is to be understoodto extend to the use of all such enantiomers and diastereomers, and tomixtures thereof in any proportion, including racemates. Formula (I) andthe formulae depicted hereinafter are intended to represent allindividual stereoisomers and all possible mixtures thereof, unlessstated or shown otherwise. In addition, compounds of formula (I) mayexist as tautomers, for example keto (CH₂C═O)

enol (CH═CHOH) tautomers or amide (NHC═O)

hydroxyimine (N═COH) tautomers. Formula (I) and the formulae depictedhereinafter are intended to represent all individual tautomers and allpossible mixtures thereof, unless stated or shown otherwise.

It is to be understood that each individual atom present in formula (I),or in the formulae depicted hereinafter, may in fact be present in theform of any of its naturally occurring isotopes, with the most abundantisotope(s) being preferred. Thus, by way of example, each individualhydrogen atom present in formula (I), or in the formulae depictedhereinafter, may be present as a ¹H, ²H (deuterium) or ³H (tritium)atom, preferably ¹H. Similarly, by way of example, each individualcarbon atom present in formula (I), or in the formulae depictedhereinafter, may be present as a ¹²C, ¹³C or ¹⁴C atom, preferably ¹²C.

In one aspect, the present invention provides a compound of formula (I)as depicted above or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, or a glucuronide derivative thereof,or a co-crystal thereof, wherein

Q represents —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NR⁶)—, —N(R⁶)—,—C(O)N(R⁶)—, —N(R⁶)C(O)—, —S(O)₂N(R⁶)— or —N(R⁶)S(O)₂—; or Q representsan optionally substituted straight or branched C₁₋₆ alkylene chainoptionally comprising one, two or three heteroatom-containing linkagesindependently selected from —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NR⁶)—,—N(R⁶)—, —C(O)N(R⁶)—, —N(R⁶)C(O)—, —S(O)₂N(R⁶)— and —N(R⁶)S(O)₂—;

Z represents C₃₋₇ cycloalkyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkenyl or heteroaryl, any of which groups may be optionallysubstituted by one or more substituents; or Z represents —Z¹—Z² or—Z¹—C(O)—Z², either of which moieties may be optionally substituted byone or more substituents; and

q, A, B, D, G, E, Y, R¹, R⁶, Z¹ and Z² are as defined above.

In another aspect, the present invention provides a compound of formula(I) as depicted above or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, or a glucuronide derivative thereof,or a co-crystal thereof, wherein

R¹ represents halogen or cyano; or C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl,aryl, aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkenyl, C₄₋₉heterobicycloalkyl, heteroaryl, heteroaryl(C₁₋₆)alkyl,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-,heteroaryl(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-heteroaryl-,(C₄₋₇)cycloalkenyl-heteroaryl-, (C₄₋₉)bicycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents; and

q, A, B, D, G, E, Q, Y and Z are as defined above.

In one embodiment, q is zero. In another embodiment, q is 1.

In one embodiment, A represents C—R². In another embodiment, Arepresents N.

In one embodiment, B represents C—R³. In another embodiment, Brepresents N.

In one embodiment, D represents C—R⁴. In another embodiment, Drepresents N.

In a first embodiment, A represents C—R², B represents C—R³ and Drepresents C—R⁴.

In a second embodiment, A represents C—R², B represents C—R³ and Drepresents N.

In a third embodiment, A represents C—R², B represents N and Drepresents C—R⁴.

In a fourth embodiment, A represents C—R², B represents N and Drepresents N.

In a fifth embodiment, A represents N, B represents C—R³ and Drepresents C—R⁴.

In a sixth embodiment, A represents N, B represents C—R³ and Drepresents N.

In a seventh embodiment, A represents N, B represents N and D representsC—R⁴.

In an eighth embodiment, A represents N, B represents N and D representsN.

Suitably, A represents C—R², and B and D are as defined above; or Arepresents N, B represents C—R³, and D is as defined above.

Suitably, A represents C—R², B represents C—R³ and D is as definedabove; or A represents N, B represents C—R³ and D represents C—R⁴.

Particular sub-classes of compounds in accordance with the presentinvention include the compounds of formula (IA-A), (IA-B), (IA-C),(IA-D), (IA-E), (IA-F) and (IA-G):

wherein q, G, E, Q, Y, Z, R¹, R², R³ and R⁴ are as defined above.

In the compounds of the invention, the moiety G is defined asrepresenting the residue of a six-membered heteroaromatic ring asspecified above. From this it is to be understood that the variable G,when taken together with the two carbon atoms of the six-membered ringto which the G-containing ring is fused, represents a six-memberedheteroaromatic ring as specified above.

Suitably, the moiety G in the compounds of the invention represents theresidue of a six-membered heteroaromatic ring selected from pyridinyl,pyridazinyl, pyrimidinyl and pyrazinyl.

In a first embodiment, the moiety G in the compounds of the inventionrepresents the residue of a pyridine ring.

In a second embodiment, the moiety G in the compounds of the inventionrepresents the residue of a pyridazine ring.

In a third embodiment, the moiety G in the compounds of the inventionrepresents the residue of a pyrimidine ring.

In a fourth embodiment, the moiety G in the compounds of the inventionrepresents the residue of a pyrazine ring.

In a fifth embodiment, the moiety G in the compounds of the inventionrepresents the residue of a triazine ring.

Particular sub-classes of compounds in accordance with the presentinvention include the compounds of formula (IB-A), (IB-B), (IB-C),(IB-D), (IB-E), (IB-F), (IB-G), (IB-H), (IB-J), (IB-K) and (IIB-L):

wherein

A, B, D, E, Q, Y, Z and R¹ are as defined above.

Suitable sub-classes of compounds in accordance with the presentinvention include the compounds of formula (IB-B), (IB-C), (IB-E),(IB-G) and (IB-H) as depicted above.

Where the compounds in accordance with the invention comprise anoptionally substituted straight or branched alkylene chain, typicalvalues thereof include methylene (—CH₂—), (methyl)methylene, ethylene(—CH₂CH₂—), (ethyl)methylene, (dimethyl)-methylene, (methyl)ethylene,propylene (—CH₂CH₂CH₂—), (propyl)methylene and (dimethyl)ethylene, anyof which chains may be optionally substituted by one or moresubstituents. Suitably, such chains are unsubstituted, monosubstitutedor disubstituted. Typically, such chains are unsubstituted ormonosubstituted. In one embodiment, such chains are unsubstituted. Inanother embodiment, such chains are monosubstituted. In a furtherembodiment, such chains are disubstituted.

Examples of typical substituents on the alkylene chain which may bepresent in a compound in accordance with the invention include halogen,cyano, trifluoromethyl, oxo, hydroxy, C₁₋₆ alkoxy, carboxy(C₁₋₆)alkoxy,trifluoromethoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, C₂₋₆alkylcarbonylamino, carboxy, benzyloxycarbonyl, tetrazolyl,aminocarbonyl, C₁₋₆ alkylaminocarbonyl and di(C₁₋₆)alkylaminocarbonyl.

Specific examples of suitable substituents on the alkylene chain whichmay be present in a compound in accordance with the invention includefluoro, cyano, trifluoromethyl, hydroxy, methoxy, carboxymethoxy, amino,acetylamino, carboxy, benzyloxycarbonyl and tetrazolyl.

In a first embodiment, E represents a covalent bond, whereby the integerY is attached directly to the six-membered ring.

In a second embodiment, E represents —O—, —S—, —S(O)—, —S(O)₂—,—S(O)(NR⁵)— or —N(R⁵)—. In a first aspect of that embodiment, Erepresents —O—. In a second aspect of that embodiment, E represents —S—.In a third aspect of that embodiment, E represents —S(O)—. In a fourthaspect of that embodiment, E represents —S(O)₂—. In a fifth aspect ofthat embodiment, E represents —S(O)(NR⁵)—. In a sixth aspect of thatembodiment, E represents —N(R⁵)—.

In a third embodiment, E represents an optionally substituted straightor branched C₁₋₄ alkylene chain. In a first aspect of that embodiment, Erepresents an optionally substituted methylene (—CH₂—) linkage. In asecond aspect of that embodiment, E represents an optionally substituted(methyl)methylene linkage. In a third aspect of that embodiment, Erepresents an optionally substituted (ethyl)methylene linkage.

Generally, E represents a covalent bond; or E represents —N(R⁵)—; or Erepresents an optionally substituted straight or branched C₁₋₄ alkylenechain.

Typically, E represents —N(R⁵)—; or E represents an optionallysubstituted straight or branched C₁₋₄ alkylene chain.

Alternatively, E represents —O—; or E represents an optionallysubstituted straight or branched C₁₋₄ alkylene chain.

Suitably, E represents a covalent bond; or E represents —N(R⁵)—; or Erepresents methylene (—CH₂—), (methyl)methylene or (ethyl)methylene, anyof which groups may be optionally substituted by one or moresubstituents.

Generally, E represents —N(R⁵)—; or E represents methylene (—CH₂—) or(methyl)methylene, either of which groups may be optionally substitutedby one or more substituents.

Alternatively, E represents —O—; or E represents methylene (—CH₂—) or(methyl)methylene, either of which groups may be optionally substitutedby one or more substituents.

Appositely, E represents methylene (—CH₂—) or (methyl)methylene, eitherof which groups may be optionally substituted by one or moresubstituents.

Selected examples of typical substituents on the linkage represented byE include halogen, trifluoromethyl, hydroxy, C₁₋₆ alkoxy,carboxy(C₁₋₆)alkoxy, trifluoromethoxy, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, C₂₋₆ alkylcarbonylamino, carboxy, benzyloxycarbonyland tetrazolyl.

Specific examples of typical substituents on the linkage represented byE include fluoro, trifluoromethyl, hydroxy, methoxy, carboxymethoxy,trifluoromethoxy, amino, methylamino, dimethylamino, acetylamino,carboxy, benzyloxycarbonyl and tetrazolyl.

Typical values of E include —N(R⁵)—, —CH₂—, —CH(OH)—, —CH(OCH₃)—,—CH(OCH₂CO₂H)—, —CH(NH₂)—, —CH(NHCOCH₃)—, —CH(CO₂H)—, —CH(CO₂benzyl)-,—CH(CH₃)—, —C(CH₃)(OH)— and —CH(CH₂CH₃)—; or E may represent a covalentbond. In addition, E may represent —O—.

Illustrative values of E include —O—, —CH₂— and —CH(CH₃)—.

Suitable values of E include —CH₂— and —CH(CH₃)—.

In one embodiment, E represents —CH₂—.

In another embodiment, E represents —CH(CH₃)—. In a particular aspect ofthat embodiment, the —CH(CH₃)— linkage represented by E is in the (S)stereochemical configuration.

In a first embodiment, Q represents a covalent bond, whereby the integerZ is attached directly to the six-membered ring.

In a second embodiment, Q represents —O—, —S—, —S(O)—, —S(O)₂—,—S(O)(NR⁶)—, —N(R⁶)—, —C(O)N(R⁶)—, —N(R⁶)C(O)—, —S(O)₂N(R⁶)— or—N(R⁶)S(O)₂—. In a first aspect of that embodiment, Q represents —O—. Ina second aspect of that embodiment, Q represents —S—. In a third aspectof that embodiment, Q represents —S(O)—. In a fourth aspect of thatembodiment, Q represents —S(O)₂—. In a fifth aspect of that embodiment,Q represents —S(O)(NR⁶)—. In a sixth aspect of that embodiment, Qrepresents —N(R⁶)—. In a seventh aspect of that embodiment, Q represents—C(O)N(R⁶)—. In an eighth aspect of that embodiment, Q represents—N(R⁶)C(O)—. In a ninth aspect of that embodiment, Q represents—S(O)₂N(R⁶)—. In a tenth aspect of that embodiment, Q represents—N(R⁶)S(O)₂—.

In a third embodiment, Q represents an optionally substituted straightor branched C₁₋₆ alkylene chain optionally comprising one, two or threeheteroatom-containing linkages independently selected from —O—, —S—,—S(O)—, —S(O)₂—, —S(O)(NR⁶)—, —N(R⁶)—, —C(O)N(R⁶)—, —N(R⁶)C(O)—,—S(O)₂N(R⁶)— and —N(R⁶)S(O)₂—. In a first aspect of that embodiment, Qrepresents an optionally substituted straight or branched C₁₋₆ alkylenechain. In a second aspect of that embodiment, Q represents an optionallysubstituted straight or branched C₁₋₆ alkylene chain comprising oneheteroatom-containing linkage independently selected from —O—, —S—,—S(O)—, —S(O)₂—, —S(O)(NR⁶)—, —N(R⁶)—, —C(O)N(R⁶)—, —N(R⁶)C(O)—,—S(O)₂N(R⁶)— and —N(R⁶)S(O)₂—. In a third aspect of that embodiment, Qrepresents an optionally substituted straight or branched C₁₋₆ alkylenechain comprising two heteroatom-containing linkages independentlyselected from —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NR⁶)—, —N(R⁶)—,—C(O)N(R⁶)—, —N(R⁶)C(O)—, —S(O)₂N(R⁶)— and —N(R⁶)S(O)₂—. In a fourthaspect of that embodiment, Q represents an optionally substitutedstraight or branched C₁₋₆ alkylene chain comprising threeheteroatom-containing linkages independently selected from —O—, —S—,—S(O)—, —S(O)₂—, —S(O)(NR⁶)—, —N(R⁶)—, —C(O)N(R⁶)—, —N(R⁶)C(O)—,—S(O)₂N(R⁶)— and —N(R⁶)S(O)₂—. In a fifth aspect of that embodiment, Qrepresents an optionally substituted straight or branched C₁₋₆ alkylenechain comprising one, two or three heteroatom-containing linkagesindependently selected from —O—, —S—, —N(R⁶)—, —C(O)N(R⁶)— and—N(R⁶)C(O)—.

Typically, Q represents a covalent bond; or Q represents —S(O)— or—S(O)₂—; or Q represents an optionally substituted straight or branchedC₁₋₆ alkylene chain optionally comprising one or twoheteroatom-containing linkages selected from —O—, —S—, —N(R⁶)—,—C(O)N(R⁶)— and —N(R⁶)C(O)—.

Generally, Q represents a covalent bond; or Q represents an optionallysubstituted straight or branched C₁₋₆ alkylene chain.

Selected examples of typical substituents on the linkage represented byQ include halogen, cyano, trifluoromethyl, hydroxy, C₁₋₆ alkoxy andamino.

Specific examples of typical substituents on the linkage represented byQ include fluoro, cyano, trifluoromethyl, hydroxy, methoxy and amino.

Suitably, Q represents a covalent bond; or Q represents —S(O)—, —S(O)₂—or —N(R⁶)—; or Q represents —CH₂—, —CH(F)—, —CF₂—, —CH(CN)—, —CH(CH₃)—,—CH(OH)—, —CH(CH₂OH)—, —CH(OCH₃)—, —CH(NH₂)—, —CH₂CH₂—, —CH(OH)CH₂—,—CH(OH)CF₂—, —CH(OCH₃)CH₂—, —CH₂O—, —CH(CH₃)O—, —C(CH₃)₂O—,—CH(CH₂CH₃)O—, —CH(CF₃)O—, —CH₂S—, —CH₂S(O)—, —CH₂S(O)₂—, —CH₂N(R⁶)—,—CH₂CH₂CH₂—, —CH(OH)CH₂CH₂—, —CH(OCH₃)CH₂CH₂—, —CH₂CH₂O—, —CH₂OCH₂—,—CH₂OCH(F)—, —CH₂OCF₂—, —CH₂OCH(CH₃)—, —CH(CH₃)OCH₂—, —CH₂OC(CH₃)₂—,—C(CH₃)₂OCH₂—, —CH₂SCH₂—, —CH₂S(O)CH₂—, —CH₂S(O)₂CH₂—, —CH₂CH₂N(R⁶)—,—CH₂N(R⁶)CH₂—, —CH₂N(R⁶)C(O)—, —CH₂CH₂OCH₂—, —CH₂CH₂N(R⁶)C(O)—,—CH₂OCH₂CH₂—, —CH₂OCH₂CF₂—, —CH₂OCH₂CH(CH₃)—, —CH₂OCH(CH₃)CH₂—,—CH₂OC(CH₃)₂CH₂—, —CH₂OCH₂CH(CH₃)CH₂—, —CH₂OCH₂CH₂O—, —CH₂OCH₂C(O)N(R⁶)—or —CH₂OCH₂CH₂OCH₂—.

Appositely, Q represents a covalent bond; or Q represents —CH₂—,—CH(CN)—, —CH(OH)—, —CH(OCH₃)—, —CH₂O—, —CH₂N(R⁶)— or —CH₂OCH₂—.

Generally, Q represents a covalent bond; or Q represents —CH₂—.

Particular values of Q include —CH₂—, —CH(OH)—, —CH₂O—, —CH₂S— and—CH₂OCH₂—. In a first embodiment, Q represents —CH₂—. In a secondembodiment, Q represents —CH(OH)—. In a third embodiment, Q represents—CH₂O—. In a fourth embodiment, Q represents —CH₂S—. In a fifthembodiment, Q represents —CH₂OCH₂—.

Generally, Y represents C₃₋₇ cycloalkyl, aryl or heteroaryl, any ofwhich groups may be optionally substituted by one or more substituents.

Typically, Y represents aryl or heteroaryl, either of which groups maybe optionally substituted by one or more substituents.

In a first embodiment, Y represents optionally substituted C₃₋₇cycloalkyl. In one aspect of that embodiment, Y represents unsubstitutedC₃₋₇ cycloalkyl. In another aspect of that embodiment, Y representsmonosubstituted C₃₋₇ cycloalkyl. In a further aspect of that embodiment,Y represents disubstituted C₃₋₇ cycloalkyl.

In a second embodiment, Y represents optionally substituted aryl. In oneaspect of that embodiment, Y represents unsubstituted aryl. In anotheraspect of that embodiment, Y represents monosubstituted aryl. In afurther aspect of that embodiment, Y represents disubstituted aryl.

In a third embodiment, Y represents optionally substituted C₃₋₇heterocycloalkyl. In one aspect of that embodiment, Y representsunsubstituted C₃₋₇ heterocycloalkyl. In another aspect of thatembodiment, Y represents monosubstituted C₃₋₇ heterocycloalkyl. In afurther aspect of that embodiment, Y represents disubstituted C₃₋₇heterocycloalkyl.

In a fourth embodiment, Y represents optionally substituted heteroaryl.In one aspect of that embodiment, Y represents unsubstituted heteroaryl.In another aspect of that embodiment, Y represents monosubstitutedheteroaryl. In a further aspect of that embodiment, Y representsdisubstituted heteroaryl.

Suitably, Y represents benzocyclobutenyl, phenyl, thienyl, thiazolyl orpyridinyl, any of which groups may be optionally substituted by one ormore substituents.

Appropriately, Y represents phenyl, thienyl or thiazolyl, any of whichgroups may be optionally substituted by one or more substituents.

Appositely, Y represents phenyl, which may be optionally substituted byone or more substituents.

Examples of optional substituents which may be present on the moiety Yinclude one, two or three substituents independently selected fromhalogen, cyano, nitro, C₁₋₆ alkyl, trifluoromethyl, hydroxy, C₁₋₆alkoxy, difluoromethoxy, trifluoromethoxy, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, (C₁₋₆)alkylsulfonyloxy, amino, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, arylamino, C₂₋₆ alkylcarbonylamino, C₁₋₆alkylsulfonylamino, formyl, C₂₋₆ alkylcarbonyl, C₃₋₆ cycloalkylcarbonyl,C₃₋₆ heterocycloalkylcarbonyl, carboxy, C₂₋₆ alkoxycarbonyl,aminocarbonyl, C₁₋₆ alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl,aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆)alkylaminosulfonyl.

Illustrative examples of optional substituents on the moiety Y includehalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy and difluoromethoxy. Additionalexamples include cyano.

Typical examples of optional substituents on the moiety Y includehalogen, cyano and difluoromethoxy.

Examples of particular substituents on the moiety Y include fluoro,chloro, bromo, cyano, nitro, methyl, isopropyl, trifluoromethyl,hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, methylthio,methylsulfinyl, methylsulfonyl, methylsulfonyloxy, amino, methylamino,tert-butylamino, dimethylamino, phenylamino, acetylamino,methylsulfonylamino, formyl, acetyl, cyclopropylcarbonyl,azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl,piperazinylcarbonyl, morpholinylcarbonyl, carboxy, methoxycarbonyl,aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl,aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.

Illustrative examples of particular substituents on the moiety Y includechloro, methyl, methoxy and difluoromethoxy. Additional examples includecyano.

Typical examples of particular substituents on the moiety Y includefluoro, chloro, cyano and difluoromethoxy.

Typical values of Y include benzocyclobutenyl, phenyl, fluorophenyl(including 2-fluorophenyl, 3-fluorophenyl and 4-fluorophenyl),chlorophenyl (including 2-chlorophenyl, 3-chlorophenyl and4-chlorophenyl), difluorophenyl (including 2,6-difluorophenyl),(chloro)(fluoro)phenyl (including 5-chloro-2-fluorophenyl and2-chloro-5-fluorophenyl), dichlorophenyl (including 2,5-dichlorophenyland 2,6-dichlorophenyl), methylphenyl (including 4-methylphenyl),dimethylphenyl (including 2,5-dimethylphenyl and 2,6-dimethylphenyl),(trifluoromethyl)phenyl [including 2-(trifluoromethyl)phenyl],(chloro)(trifluoromethyl)phenyl [including5-chloro-2-(trifluoromethyl)phenyl], (methyl)-(trifluoromethyl)phenyl[including 2-methyl-5-(trifluoromethyl)phenyl],bis(trifluoro-methyl)phenyl [including 2,5-bis(trifluoromethyl)phenyl],methoxyphenyl (including 2-methoxyphenyl), (difluoromethoxy)phenyl[including 2-(difluoromethoxy)phenyl and 3-(difluoromethoxy)phenyl],(difluoromethoxy)(fluoro)phenyl [including2-(difluoro-methoxy)-5-fluorophenyl and2-(difluoromethoxy)-6-fluorophenyl], (chloro)(difluoro-methoxy)phenyl[including 5-chloro-2-(difluoromethoxy)phenyl and6-chloro-2-(difluoromethoxy)phenyl], (cyano)(difluoromethoxy)phenyl[including 6-cyano-2-(difluoromethoxy)phenyl], (trifluoromethoxy)phenyl[including 2-(trifluoromethoxy)-phenyl], methylsulfonyloxyphenyl,(amino)(chloro)phenyl (including 5-amino-2-chlorophenyl), methylthienyl(including 3-methylthien-2-yl), methylthiazolyl (including2-methyl-1,3-thiazol-4-yl), (chloro)(methyl)thiazolyl (including5-chloro-2-methyl-1,3-thiazol-4-yl), dimethylthiazolyl (including2,4-dimethyl-1,3-thiazol-5-yl) and pyridinyl (including pyridin-3-yl andpyridin-4-yl).

Illustrative values of Y include phenyl, chlorophenyl, methylphenyl,methoxyphenyl and (difluoromethoxy)phenyl.

Selected values of Y include dichlorophenyl, dimethylphenyl,(difluoromethoxy)-phenyl, (difluoromethoxy)(fluoro)phenyl,(chloro)(difluoromethoxy)phenyl, (cyano)-(difluoromethoxy)phenyl,methylsulfonyloxyphenyl, methylthienyl and dimethylthiazolyl.

In one embodiment, Y represents 2,5-dichlorophenyl.

In another embodiment, Y represents phenyl.

In another embodiment, Y represents 2-chlorophenyl.

In another embodiment, Y represents 2-methylphenyl.

In another embodiment, Y represents 2,5-dimethylphenyl.

In another embodiment, Y represents 2-methoxyphenyl.

In a particular embodiment, Y represents 2-(difluoromethoxy)phenyl.

In another embodiment, Y represents (difluoromethoxy)(fluoro)phenyl.

In another embodiment, Y represents (chloro)(difluoromethoxy) phenyl.

In another embodiment, Y represents (cyano)(difluoromethoxy) phenyl.

In another embodiment, Y represents 3-methylthien-2-yl.

In another embodiment, Y represents 2,4-dimethyl-1,3-thiazol-5-yl.

In one embodiment, Z represents hydrogen.

In another embodiment, Z is other than hydrogen.

In a selected embodiment, Z represents hydrogen; or Z represents C₁₋₆alkyl, C₃₋₇ cycloalkyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkenyl or heteroaryl, any of which groups may be optionallysubstituted by one or more substituents; or Z represents —Z¹—Z² or—Z¹—C(O)—Z², either of which moieties may be optionally substituted byone or more substituents.

In a further embodiment, Z represents C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl,C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl or heteroaryl, any ofwhich groups may be optionally substituted by one or more substituents;or Z represents —Z¹—Z² or —Z¹—C(O)—Z², either of which moieties may beoptionally substituted by one or more substituents.

Suitably, Z represents hydrogen; or Z represents C₁₋₆ alkyl, aryl orheteroaryl, any of which groups may be optionally substituted by one ormore substituents; or Z represents —Z¹—Z², which moiety may beoptionally substituted by one or more substituents.

Appositely, Z represents hydrogen; or Z represents C₁₋₆ alkyl, whichgroup may be optionally substituted by one or more substituents.

Typically, Z represents hydrogen, fluoro or trifluoromethyl; or Zrepresents methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,phenyl, tetrahydrofuranyl, pyrrolidinyl, indolinyl, tetrahydropyranyl,piperidinyl, 1,2,3,4-tetrahydroquinolinyl, morpholinyl, azocanyl,thiazolinyl, furyl, thienyl, pyrazolyl, 4,5,6,7-tetrahydroindazolyl,benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, imidazolyl,benzimidazolyl, [1,2,4]triazolo[1,5-c]-pyrimidinyl, tetrazolyl,pyridinyl, quinolinyl, isoquinolinyl, phthalazinyl, pyrimidinyl orpyrazinyl, any of which groups may be optionally substituted by one ormore substituents; or Z represents —Z¹—Z² or —Z¹—C(O)—Z², either ofwhich moieties may be optionally substituted by one or moresubstituents.

The moiety Z¹ represents a divalent radical derived from an aryl, C₃₋₇heterocycloalkyl or heteroaryl group, any of which groups may beoptionally substituted by one or more substituents. Typically, themoiety Z¹ represents a divalent radical derived from a phenyl,pyrrolidinyl, piperazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolylor pyridinyl group, any of which groups may be optionally substituted byone or more substituents. Typical values of the moiety Z¹ include thegroups of formula (Za), (Zb), (Zc), (Zd), (Ze), (Zf), (Zg), (Zh), (Zj)and (Zk):

wherein

the symbols # represent the points of attachment of the moiety Z¹ to theremainder of the molecule; and

the asterisks (*) represent the site of attachment of optionalsubstituents.

Particular values of the moiety Z¹ include the groups of formula (Za),(Zc), (Ze), (Zf), (Zg), (Zh) and (Zj) as depicted above.

The moiety Z² represents aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkenyl or heteroaryl, any of which groups may be optionallysubstituted by one or more substituents. Typically, Z² representsphenyl, pyrrolidinyl, oxazolidinyl, imidazolidinyl, morpholinyl,imidazolinyl, thiazolyl, imidazolyl, tetrazolyl or pyridinyl, any ofwhich groups may be optionally substituted by one or more substituents.

Examples of optional substituents which may be present on the moiety Z,Z¹ or Z² include one, two or three substituents independently selectedfrom halogen, cyano, nitro, C₁₋₆ alkyl, trifluoromethyl, oxo, hydroxy,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, difluoro-methoxy, trifluoromethoxy,C₁₋₃ alkylenedioxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,di(C₁₋₆)alkylamino(C₁₋₆)alkyl, C₂₋₆ alkylcarbonylamino, C₁₋₆alkylsulfonylamino, formyl, C₂₋₆ alkylcarbonyl, carboxy, C₂₋₆alkoxycarbonyl, aminocarbonyl, C₁₋₆ alkylaminocarbonyl,di(C₁₋₆)alkylaminocarbonyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl,di(C₁₋₆)alkylaminosulfonyl, aminocarbonylamino and hydrazinocarbonyl.

Examples of particular substituents on the moiety Z, Z¹ or Z² includefluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl,trifluoromethyl, oxo, hydroxy, hydroxymethyl, methoxy, difluoromethoxy,trifluoromethoxy, methylenedioxy, methylthio, methylsulfinyl,methylsulfonyl, amino, methylamino, tert-butylamino, dimethylamino,dimethylaminomethyl, dimethylaminoethyl, acetylamino,methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl,tert-butoxycarbonyl, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl,dimethylaminosulfonyl, aminocarbonylamino and hydrazinocarbonyl.

Typical values of Z² include phenyl, hydroxyphenyl, oxopyrrolidinyl,dioxo-pyrrolidinyl, (hydroxy)(oxo)pyrrolidinyl,(amino)(oxo)pyrrolidinyl, (oxo)oxazolidinyl, oxoimidazolidinyl,morpholinyl, imidazolinyl, methylthiazolyl, formylthiazolyl, imidazolyl,tetrazolyl and pyridinyl.

Selected values of Z² include oxopyrrolidinyl and (oxo)oxazolidinyl. Inone embodiment, Z² represents oxopyrrolidinyl. In another embodiment, Z²represents (oxo)oxazolidinyl.

Typical values of Z include hydrogen, fluoro, trifluoromethyl, methyl,ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, cyclopropyl,cyclopentyl, cyclohexyl, oxo-cyclohexyl, phenyl, bromophenyl,cyanophenyl, nitrophenyl, methoxyphenyl, difluoro-methoxyphenyl,trifluoromethoxyphenyl, methylenedioxyphenyl, methylsulfonylphenyl,dimethylaminophenyl, acetylaminophenyl, methylsulfonylaminophenyl,carboxyphenyl, aminocarbonylphenyl, methylaminocarbonylphenyl,dimethylaminocarbonylphenyl, aminocarbonylaminophenyl,tetrahydrofuranyl, oxopyrrolidinyl, dimethylamino-pyrrolidinyl,tert-butoxycarbonylpyrrolidinyl, indolinyl, tetrahydropyranyl,piperidinyl, ethylpiperidinyl, tert-butoxycarbonylpiperidinyl, aminocarbonylpiperidinyl, 2-oxo-3,4-dihydroquinolinyl, morpholinyl, azocanyl,oxothiazolinyl, furyl, hydroxymethylfuryl, thienyl, methylpyrazolyl,dimethylpyrazolyl, 4,5,6,7-tetrahydroindazolyl, benzoxazolyl,methylisoxazolyl, dimethylisoxazolyl, methylthiazolyl, aminothiazolyl,benzothiazolyl, methylbenzothiazolyl, aminobenzothiazolyl, imidazolyl,methylimidazolyl, methyl-benzimidazolyl,dimethyl[1,2,4]triazolo[1,5-c]pyrimidinyl, dimethylaminoethyltetrazolyl,pyridinyl, fluoropyridinyl, chloropyridinyl, cyanopyridinyl,methylpyridinyl, (cyano)-(methyl)pyridinyl, trifluoromethylpyridinyl,oxopyridinyl, methoxypyridinyl, methylsulfonylpyridinyl,dimethylaminomethylpyridinyl, acetylaminopyridinyl, carboxypyridinyl,methoxycarbonylpyridinyl, aminocarbonylpyridinyl,(aminocarbonyl)(fluoro)-pyridinyl, methylaminocarbonylpyridinyl,dimethylaminocarbonylpyridinyl, hydrazino-carbonylpyridinyl, quinolinyl,isoquinolinyl, (methyl)(oxo)phthalazinyl, pyrimidinyl, pyrazinyl,oxopyrrolidinylphenyl, dioxopyrrolidinylphenyl,(hydroxy)(oxo)pyrrolidinylphenyl, (amino)(oxo)pyrrolidinylphenyl,(oxo)oxazolidinylphenyl, oxoimidazolidinyl-phenyl, imidazolinylphenyl,methylthiazolylphenyl, formylthiazolylphenyl, imidazolyl-phenyl,tetrazolylphenyl, phenylpyrrolidinyl, hydroxyphenylpiperazinyl,(methyl)-(phenyl)pyrazolyl, oxoimidazolidinylthiazolyl,hydroxyphenyltriazolyl, morpholinyl-tetrazolyl,oxopyrrolidinylpyridinyl, (oxo)oxazolidinylpyridinyl,oxoimidazolidinyl-pyridinyl, pyridinylthiazolyl, pyridinyltetrazolyl andmorpholinylcarbonylphenyl.

Particular values of Z include hydrogen, methyl, methylsulfonylphenyl,pyridinyl, methylsulfonylpyridinyl, oxopyrrolidinylphenyl,(hydroxy)(oxo)pyrrolidinylphenyl and (oxo)oxazolidinylphenyl.

Selected values of Z include hydrogen and methyl.

In a first embodiment, Z represents hydrogen. In a second embodiment, Zrepresents methyl. In a third embodiment, Z representsmethylsulfonylphenyl. In one aspect of that embodiment, Z represents3-(methylsulfonyl)phenyl. In another aspect of that embodiment, Zrepresents 4-(methylsulfonyl)phenyl. In a fourth embodiment, Zrepresents pyridinyl. In one aspect of that embodiment, Z representspyridin-4-yl. In a fifth embodiment, Z represents oxopyrrolidinylphenyl.In one aspect of that embodiment, Z represents3-(2-oxopyrrolidin-1-yl)phenyl. In a sixth embodiment, Z represents(hydroxy)(oxo)pyrrolidinylphenyl. In one aspect of that embodiment, Zrepresents 3-(3-hydroxy-2-oxopyrrolidin-1-yl)phenyl. In another aspectof that embodiment, Z represents3-(4-hydroxy-2-oxopyrrolidin-1-yl)phenyl. In a seventh embodiment, Zrepresents (oxo)oxazolidinylphenyl. In one aspect of that embodiment, Zrepresents 3-(2-oxo-oxazolidinyl-3-yl)phenyl. In an eighth embodiment, Zrepresents methylsulfonylpyridinyl.

Suitably, R¹, R², R³ and R⁴ independently represent hydrogen, halogen,cyano, trifluoromethyl or —CO₂R^(d); or C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl,C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl, heteroaryl,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-,heteroaryl-(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl(C₁₋₆)alkyl-heteroaryl-, (C₄₋₇)cycloalkenyl-heteroaryl-,(C₄₋₉)bicycloalkyl-heteroaryl-, (C₃₋₇)heterocycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-hetero aryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

Typically, R¹, R², R³ and R⁴ independently represent hydrogen; or arylor heteroaryl, either of which groups may be optionally substituted byone or more substituents.

Examples of optional substituents which may be present on R¹, R², R³ orR⁴ include one, two or three substituents independently selected fromhalogen, halo-(C₁₋₆)alkyl, cyano, cyano(C₁₋₆)alkyl, nitro,nitro(C₁₋₆)alkyl, C₁₋₆ alkyl, difluoromethyl, trifluoromethyl,difluoroethyl, trifluoroethyl, C₂₋₆ alkenyl, hydroxy,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, difluoromethoxy, trifluoromethoxy,trifluoroethoxy, carboxy(C₃₋₇)cycloalkyloxy, C₁₋₃ alkylenedioxy, C₁₋₆alkoxy(C₁₋₆)alkyl, pentafluorothio, C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl,C₁₋₆ alkylsulphonyl, (C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, oxo, amino,amino-(C₁₋₆)alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,hydroxy(C₁₋₆)alkylamino, C₁₋₆ alkoxyamino, (C₁₋₆)alkoxy(C₁₋₆)alkylamino,[(C₁₋₆)alkoxy](hydroxy)(C₁₋₆)alkylamino,[(C₁₋₆)alkylthio](hydroxy)(C₁₋₆)alkylamino,N—[(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino,di(C₁₋₆)alkylamino(C₁₋₆)alkylamino,N-[di(C₁₋₆)alkylamino(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)-alkyl]amino,hydroxy(C₁₋₆)alkyl(C₃₋₇)cycloalkylamino,(hydroxy)[(C₃₋₇)cycloalkyl(C₁₋₆)-alkyl]amino,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkylamino,oxo(C₃₋₇)heterocycloalkyl(C₁₋₆)alkylamino, (C₁₋₆)alkylheteroarylamino,heteroaryl(C₁₋₆)alkylamino, (C₁₋₆)alkylheteroaryl(C₁₋₆)-alkylamino, C₂₋₆alkylcarbonylamino, N—[(C₁₋₆)alkyl]-N—[(C₂₋₆)alkylcarbonyl]amino,(C₂₋₆)-alkylcarbonylamino(C₁₋₆)alkyl, C₃₋₆ alkenylcarbonylamino,bis[(C₃₋₆)alkenylcarbonyl]-amino,N—[(C₁₋₆)alkyl]-N—[(C₃₋₇)cycloalkylcarbonyl]amino, C₂₋₆alkoxycarbonylamino, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkylamino, C₁₋₆alkylaminocarbonylamino, C₁₋₆ alkylsulphonylamino,N—[(C₁₋₆)alkyl]-N—[(C₁₋₆)alkylsulphonyl]amino,bis[(C₁₋₆)alkylsulphonyl]amino,N—[(C₁-C₆)alkyl]-N-[carboxy(C₁₋₆)alkyl]amino,carboxy(C₃₋₇)cycloalkylamino, carboxy-(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,formyl, C₂₋₆ alkylcarbonyl, (C₃₋₇)cycloalkylcarbonyl, phenylcarbonyl,(C₂₋₆)alkylcarbonyloxy(C₁₋₆)alkyl, carboxy, carboxy(C₁₋₆)alkyl, C₂₋₆alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonylmethylidenyl, acarboxylic acid isostere or prodrug moiety Ω, —(C₁₋₆)alkyl-Ω,aminocarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxy(C₁₋₆)alkylaminocarbonyl,di(C₁₋₆)alkylaminocarbonyl, aminocarbonyl(C₁₋₆)alkyl, aminosulphonyl,di(C₁₋₆)alkylaminosulphonyl, (C₁₋₆)alkylsulphoximinyl and[(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]-sulphoximinyl.

By the expression “carboxylic acid isostere or prodrug moiety” is meantany functional group, structurally distinct from a carboxylic acidmoiety, that will be recognised by a biological system as being similarto, and thus capable of mimicking, a carboxylic acid moiety, or will bereadily convertible by a biological system in vivo into a carboxylicacid moiety. A synopsis of some common carboxylic acid isosteres ispresented by N. A. Meanwell in J. Med. Chem., 2011, 54, 2529-2591 (cf.in particular FIGS. 25 and 26). An alternative carboxylic acid isostereis described by N Pemberton et al. in ACS Med. Chem. Lett., 2012, 3,574-578. Typical examples of suitable carboxylic acid isostere orprodrug moieties represented by Ω include the functional groups offormula (i) to (xliii):

wherein

the asterisk (*) represents the site of attachment to the remainder ofthe molecule;

n is zero, 1 or 2;

X represents oxygen or sulphur;

R^(f) represents hydrogen, C₁₋₆ alkyl or —CH₂CH(OH)CH₂OH;

R^(g) represents C₁₋₆ alkyl, trifluoromethyl, —CH₂CH₂F, —CH₂CHF₂,—CH₂CF₃ or —CF₂CF₃;

R^(h) represents hydrogen, cyano or —CO₂R^(d), in which R^(d) is asdefined above; and

R^(j) represents hydrogen or halogen.

In one embodiment, n is zero. In another embodiment, n is 1. In afurther embodiment, n is 2.

In one embodiment, X represents oxygen. In another embodiment, Xrepresents sulphur.

In one embodiment, R^(f) represents hydrogen. In another embodiment,R^(f) represents C₁₋₆ alkyl, especially methyl. In a further embodiment,R^(f) is —CH₂CH(OH)CH₂OH.

In one embodiment, R^(g) represents C₁₋₆ alkyl, especially methyl. Inanother embodiment, R^(g) represents trifluoromethyl, —CH₂CH₂F,—CH₂CHF₂, —CH₂CF₃ or —CF₂CF₃.

In a first aspect of that embodiment, R^(g) represents trifluoromethyl.In a second aspect of that embodiment, R^(g) represents —CH₂CH₂F. In athird aspect of that embodiment, R^(g) represents —CH₂CHF₂. In a fourthaspect of that embodiment, R^(g) represents —CH₂CF₃. In a fifth aspectof that embodiment, R^(g) represents —CF₂CF₃.

In one embodiment, R^(h) is hydrogen. In another embodiment, R^(h)represents cyano. In a further embodiment, R^(h) represents —CO₂R^(d),especially methoxycarbonyl.

In one embodiment, R^(j) represents hydrogen. In another embodiment,R^(j) represents halogen, especially chloro.

In a selected embodiment, Ω represents tetrazolyl, especially a C-linkedtetrazolyl moiety of formula (xxiv) or (xxv) as depicted above, inparticular a group of formula (xxiv) as depicted above.

In another embodiment, Ω represents C₁₋₆ alkylsulphonylaminocarbonyl,i.e. a moiety of formula (iii) as depicted above wherein R^(g)represents C₁₋₆ alkyl.

In another embodiment, Ω represents C₁₋₆ alkylaminosulphonyl, i.e. amoiety of formula (x) as depicted above wherein R^(g) represents C₁₋₆alkyl.

In a further embodiment, Ω represents (C₁₋₆)alkylcarbonylaminosulphonyl,i.e. a moiety of formula (v) as depicted above wherein R^(g) representsC₁₋₆ alkyl.

Typical examples of optional substituents which may be present on R¹,R², R³ or R⁴ include one, two or three substituents independentlyselected from hydroxy(C₁₋₆)alkyl and C₁₋₆ alkylsulphonyl.

Examples of particular substituents on R¹, R², R³ or R⁴ include fluoro,chloro, bromo, fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitro,nitromethyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethenyl,hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy,difluoromethoxy, trifluoromethoxy, trifluoroethoxy,carboxycyclobutyloxy, methylenedioxy, ethylenedioxy, methoxymethyl,methoxyethyl, pentafluorothio, methylthio, methylsulphinyl,methylsulphonyl, methylsulphonylethyl, oxo, amino, aminomethyl,aminoisopropyl, methylamino, ethylamino, dimethylamino,hydroxyethylamino, hydroxypropylamino, (hydroxy)(methyl)propylamino,methoxyamino, methoxyethylamino, (hydroxy)(methoxy)(methyl)propylamino,(hydroxy)(methylthio)butylamino, N-(hydroxyethyl)-N-(methyl)amino,dimethylaminoethylamino, (dimethylamino)(methyl)-propylamino,N-(dimethylaminoethyl)-N-(hydroxyethyl)amino,hydroxymethyl-cyclopentylamino, hydroxycyclobutylmethylamino,(cyclopropyl)(hydroxy)propylamino, morpholinylethylamino,oxopyrrolidinylmethylamino, ethyloxadiazolylamino,methyl-thiadiazolylamino, thiazolylmethylamino, thiazolylethylamino,pyrimidinylmethylamino, methylpyrazolylmethylamino, acetylamino,N-acetyl-N-methylamino, N-isopropyl-carbonyl-N-methylamino,acetylaminomethyl, ethenylcarbonylamino, bis(ethenyl-carbonyl)amino,N-cyclopropylcarbonyl-N-methylamino, methoxycarbonylamino,ethoxycarbonylamino, tert-butoxycarbonylamino,methoxycarbonylethylamino, ethylaminocarbonylamino,butylaminocarbonylamino, methylsulphonylamino,N-methyl-N-(methylsulphonyl)amino, bis(methylsulphonyl)amino,N-(carboxymethyl)-N-methylamino, N-(carboxyethyl)-N-methylamino,carboxycyclopentylamino, carboxycyclopropylmethylamino, formyl, acetyl,isopropylcarbonyl, cyclobutylcarbonyl, phenylcarbonyl, acetoxyisopropyl,carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl,n-butoxycarbonyl, tert-butoxycarbonyl, methoxycarbonylmethyl,ethoxycarbonylmethyl, ethoxycarbonylethyl, morpholinylethoxycarbonyl,ethoxycarbonylmethylidenyl, methylsulphonylaminocarbonyl,acetylaminosulphonyl, methoxyaminocarbonyl, tetrazolyl,tetrazolylmethyl, hydroxyoxadiazolyl, aminocarbonyl,methylamino-carbonyl, hydroxyethylaminocarbonyl, dimethylaminocarbonyl,aminocarbonylmethyl, aminosulphonyl, methylaminosulphonyl,dimethylaminosulphonyl, methylsulphoximinyl and(methyl)(N-methyl)sulphoximinyl.

Typical examples of particular substituents which may be present on R¹,R², R³ or R⁴ include one, two or three substituents independentlyselected from hydroxyisopropyl and methylsulphonyl.

Typically, R¹ represents hydrogen, halogen, cyano or —CO₂R^(d); or C₁₋₆alkyl, C₂₋₆ alkynyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkenyl, heteroaryl, (C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-,heteroaryl(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl(C₁₋₆)alkyl-heteroaryl-, (C₄₋₇)cycloalkenyl-heteroaryl-,(C₄₋₉)bicycloalkyl-heteroaryl-, (C₃₋₇)heterocycloalkyl-heteroaryl-,(C₃-C₇)heterocycloalkyl(C₁₋₆)alkyl-hetero aryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

Suitably, R¹ represents halogen, cyano or —CO₂R^(d); or C₁₋₆ alkyl, C₂₋₆alkynyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl,heteroaryl, (C₃₋₇)heterocycloalkyl-(C₁₋₆)alkyl-aryl-,heteroaryl(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl(C₁₋₆)alkyl-hetero aryl-,(C₄₋₇)cycloalkenyl-heteroaryl-, (C₄₋₉)bicycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl-hetero aryl-,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

Generally, R¹ represents halogen or cyano; or C₁₋₆ alkyl, C₂₋₆ alkynyl,aryl, C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl, heteroaryl,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-,heteroaryl(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-hetero aryl-, (C₄₋₇)cyclo alkenyl-heteroaryl-, (C₄₋₉)bicycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-hetero aryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

More generally, R¹ represents halogen; or R¹ represents aryl, C₃₋₇heterocycloalkyl, heteroaryl, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl-heteroaryl-, (C₄₋₉)heterobicycloalkyl-heteroaryl-or (C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

Appositely, R¹ represents hydrogen; or R¹ represents aryl or heteroaryl,either of which groups may be optionally substituted by one or moresubstituents.

In a first embodiment, R¹ represents hydrogen.

In a second embodiment, R¹ represents halogen. In one aspect of thatembodiment, R¹ represents bromo.

In a third embodiment, R¹ represents cyano.

In a fourth embodiment, R¹ represents —CO₂R^(d).

In a fifth embodiment, R¹ represents optionally substituted C₁₋₆ alkyl.In one aspect of that embodiment, R¹ represents optionally substitutedethyl.

In a sixth embodiment, R¹ represents optionally substituted C₂₋₆alkynyl. In one aspect of that embodiment, R¹ represents optionallysubstituted butynyl.

In a seventh embodiment, R¹ represents optionally substituted aryl. Inone aspect of that embodiment, R¹ represents optionally substitutedphenyl.

In an eighth embodiment, R¹ represents optionally substituted C₃₋₇heterocycloalkyl.

In a ninth embodiment, R¹ represents optionally substituted C₃₋₇heterocycloalkenyl.

In a tenth embodiment, R¹ represents optionally substituted heteroaryl.In selected aspects of that embodiment, R¹ represents benzofuryl,thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, thiazolyl,imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl orpyrazinyl, any of which groups may be optionally substituted by one ormore substituents.

In an eleventh embodiment, R¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl(C₁₋₆)alkyl-aryl-. In a first aspect of thatembodiment, R¹ represents optionally substitutedpyrrolidinylmethylphenyl-. In a second aspect of that embodiment, R¹represents optionally substituted piperazinylmethylphenyl-.

In a twelfth embodiment, R¹ represents optionally substitutedheteroaryl(C₃₋₇)-heterocycloalkyl-. In one aspect of that embodiment, R¹represents optionally substituted pyridinylpiperazinyl-.

In a thirteenth embodiment, R¹ represents optionally substituted(C₃₋₇)cycloalkyl-heteroaryl-. In a first aspect of that embodiment, R¹represents optionally substituted cyclohexylpyrazolyl-. In a secondaspect of that embodiment, R¹ represents optionally substitutedcyclohexylpyridinyl-. In a third aspect of that embodiment, R¹represents optionally substituted cyclopropylpyrimidinyl-. In a fourthaspect of that embodiment, R¹ represents optionally substitutedcyclobutylpyrimidinyl-. In a fifth aspect of that embodiment, R¹represents optionally substituted cyclopentylpyrimidinyl-. In a sixthaspect of that embodiment, R¹ represents optionally substitutedcyclohexylpyrimidinyl-. In a seventh aspect of that embodiment, R¹represents optionally substituted cyclohexylpyrazinyl-.

In a fourteenth embodiment, R¹ represents optionally substituted(C₄₋₇)-cycloalkenyl-heteroaryl-.

In a fifteenth embodiment, R¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl-heteroaryl-. In a first aspect of thatembodiment, R¹ represents optionally substituted pyrrolidinylpyridinyl-.In a second aspect of that embodiment, R¹ represents optionallysubstituted tetrahydropyranylpyridinyl-. In a third aspect of thatembodiment, R¹ represents optionally substituted piperidinylpyridinyl-.In a fourth aspect of that embodiment, R¹ represents optionallysubstituted piperazinylpyridinyl-. In a fifth aspect of that embodiment,R¹ represents optionally substituted morpholinylpyridinyl-. In a sixthaspect of that embodiment, R¹ represents optionally substitutedthiomorpholinylpyridinyl-. In a seventh aspect of that embodiment, R¹represents optionally substituted diazepanylpyridinyl-. In an eighthaspect of that embodiment, R¹ represents optionally substitutedoxetanylpyrimidinyl-. In a ninth aspect of that embodiment, R¹represents optionally substituted azetidinylpyrimidinyl-. In a tenthaspect of that embodiment, R¹ represents optionally substitutedtetrahydrofuranylpyrimidinyl-. In an eleventh aspect of that embodiment,R¹ represents optionally substituted pyrrolidinylpyrimidinyl-. In atwelfth aspect of that embodiment, R¹ represents optionally substitutedtetrahydropyranylpyrimidinyl-. In a thirteenth aspect of thatembodiment, R¹ represents optionally substitutedpiperidinylpyrimidinyl-. In a fourteenth aspect of that embodiment, R¹represents optionally substituted piperazinylpyrimidinyl-. In afifteenth aspect of that embodiment, R¹ represents optionallysubstituted morpholinylpyrimidinyl-. In a sixteenth aspect of thatembodiment, R¹ represents optionally substitutedthiomorpholinylpyrimidinyl-. In a seventeenth aspect of that embodiment,R¹ represents optionally substituted azepanylpyrimidinyl-. In aneighteenth aspect of that embodiment, R¹ represents optionallysubstituted oxazepanylpyrimidinyl-. In a nineteenth aspect of thatembodiment, R¹ represents optionally substituted diazepanylpyrimidinyl-.In a twentieth aspect of that embodiment, R¹ represents optionallysubstituted thiadiazepanylpyrimidinyl-. In a twenty-first aspect of thatembodiment, R¹ represents optionally substituted oxetanylpyrazinyl-. Ina twenty-second aspect of that embodiment, R¹ represents optionallysubstituted piperidinylpyrazinyl-.

In a sixteenth embodiment, R¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-. In a first aspect ofthat embodiment, R¹ represents optionally substitutedmorpholinylmethylthienyl-. In a second aspect of that embodiment, R¹represents optionally substituted morpholinylethylpyrazolyl-.

In a seventeenth embodiment, R¹ represents optionally substituted(C₃₋₇)-heterocycloalkenyl-heteroaryl-.

In an eighteenth embodiment, R¹ represents optionally substituted(C₄₋₉)-heterobicycloalkyl-heteroaryl-.

In a nineteenth embodiment, R¹ represents optionally substituted(C₄₋₉)-spiroheterocycloalkyl-heteroaryl-.

In a twentieth embodiment, R¹ represents optionally substituted(C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-heteroaryl-. In one aspect of thatembodiment, R¹ represents optionally substitutedcyclohexylmethylpyrimidinyl-.

In a twenty-first embodiment, R¹ represents optionally substituted(C₄₋₉)-bicycloalkyl-heteroaryl-.

Appositely, R¹ represents hydrogen, bromo, iodo or —CO₂R^(d); or ethyl,butynyl, phenyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,1,2,3,6-tetrahydropyridinyl, benzofuryl, thienyl, indolyl, pyrazolyl,indazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, quinolinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethylphenyl,piperazinylmethylphenyl, pyridinylpiperazinyl, cyclohexylpyrazolyl,cyclohexylpyridinyl, cyclopropylpyrimidinyl, cyclobutylpyrimidinyl,cyclopentylpyrimidinyl, cyclohexylpyrimidinyl, cyclohexylpyrazinyl,cyclohexylmethylpyrimidinyl, cyclohexenylpyridinyl,cyclohexenylpyrimidinyl, bicyclo[3.1.0]hexanylpyridinyl,bicyclo[3.1.0]hexanylpyrimidinyl, bicyclo[4.1.0]heptanylpyrimidinyl,bicyclo[2.2.2]octanylpyrimidinyl, pyrrolidinylpyridinyl,tetrahydropyranylpyridinyl, piperidinylpyridinyl, piperazinylpyridinyl,morpholinylpyridinyl, thiomorpholinylpyridinyl, diazepanylpyridinyl,oxetanylpyrimidinyl, azetidinylpyrimidinyl,tetrahydrofuranylpyrimidinyl, pyrrolidinylpyrimidinyl,tetrahydropyranylpyrimidinyl, piperidinylpyrimidinyl,piperazinylpyrimidinyl,hexahydro-[1,2,5]thiadiazolo[2,3-c]pyrazinylpyrimidinyl,morpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, azepanylpyrimidinyl,oxazepanylpyrimidinyl, diazepanylpyrimidinyl, thiadiazepanylpyrimidinyl,oxetanylpyrazinyl, piperidinylpyrazinyl, morpholinylmethylthienyl,morpholinylethylpyrazolyl, 3-azabicyclo[3.1.0]-hexanylpyridinyl,3-azabicyclo[3.1.0]hexanylpyridazinyl,3-azabicyclo[3.1.0]hexanylpyrimidinyl,2-oxa-5-azabicyclo[2.2.1]heptanylpyrimidinyl,3-azabicyclo[3.1.1]heptanylpyrimidinyl,6-oxa-3-azabicyclo[3.1.1]heptanylpyrimidinyl,3-azabicyclo[4.1.0]heptanylpyridinyl,3-azabicyclo[4.1.0]heptanylpyrimidinyl,2-oxabicyclo[2.2.2]octanylpyrimidinyl,3-azabicyclo[3.2.1]octanylpyrimidinyl,8-azabicyclo[3.2.1]octanylpyrimidinyl,3-oxa-8-azabicyclo[3.2.1]octanylpyrimidinyl,3,6-diazabicyclo[3.2.2]-nonanylpyrimidinyl,3-oxa-7-azabicyclo[3.3.1]nonanylpyrimidinyl,3,7-dioxa-9-azabicyclo[3.3.1]nonanylpyrimidinyl,5-azaspiro[2.3]hexanylpyrimidinyl, 5-azaspiro-[2.4]heptanylpyrimidinyl,2-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro[3.3]-heptanylpyrimidinyl,3-oxa-6-azaspiro[3.3]heptanylpyrimidinyl,6-thia-2-azaspiro[3.3]-heptanylpyrimidinyl,2-oxa-6-azaspiro[3.4]octanylpyrimidinyl,2-oxa-6-azaspiro[3.5]-nonanylpyrimidinyl,2-oxa-7-azaspiro[3.5]nonanylpyrimidinyl or2,4,8-triazaspiro[4.5]-decanylpyrimidinyl, any of which groups may beoptionally substituted by one or more substituents.

Appropriately, R¹ represents hydrogen; or R¹ represents phenyl orpyrimidinyl, either of which groups may be optionally substituted by oneor more substituents.

Typical examples of optional substituents on R¹ include one, two orthree substituents independently selected from halogen, halo(C₁₋₆)alkyl,cyano, cyano(C₁₋₆)alkyl, nitro(C₁₋₆)alkyl, C₁₋₆ alkyl, trifluoromethyl,difluoroethyl, trifluoroethyl, C₂₋₆ alkenyl, hydroxy,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, trifluoroethoxy,carboxy(C₃₋₇)cycloalkyloxy, pentafluorothio, C₁₋₆ alkylthio, C₁₋₆alkylsulphonyl, (C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, oxo, amino,amino(C₁₋₆)alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,(C₁₋₆)alkoxy(C₁₋₆)alkylamino,N—[(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino,(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, C₁₋₆ alkylsulphonylamino,N—[(C₁₋₆)alkyl]-N—[(C₁₋₆)alkylsulphonyl]amino,bis[(C₁₋₆)alkylsulphonyl]amino,N—[(C₁₋₆)alkyl]-N-[carboxy(C₁₋₆)alkyl]amino,carboxy(C₃₋₇)cycloalkylamino, carboxy(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,formyl, C₂₋₆ alkylcarbonyl, (C₂₋₆)alkyl-carbonyloxy(C₁₋₆)alkyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonylmethylidenyl, acarboxylic acid isostere or prodrug moiety Ω as defined herein,—(C₁₋₆)alkyl-Ω, aminocarbonyl, aminosulphonyl, (C₁₋₆)alkylsulphoximinyland [(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]sulphoximinyl.

Suitable examples of optional substituents on R¹ include one, two orthree substituents independently selected from hydroxy(C₁₋₆)alkyl andC₁₋₆ alkylsulphonyl.

Typical examples of particular substituents on R¹ include one, two orthree substituents independently selected from fluoro, chloro,fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitromethyl, methyl,ethyl, isopropyl, trifluoromethyl, difluoroethyl, ethenyl, hydroxy,hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy, trifluoroethoxy,carboxycyclobutyloxy, pentafluorothio, methylthio, methylsulphonyl,methylsulphonylethyl, oxo, amino, aminomethyl, aminoisopropyl,methylamino, dimethylamino, methoxyethylamino,N-(hydroxyethyl)-N-(methyl)amino, acetylaminomethyl,methylsulphonylamino, N-methyl-N-(methylsulphonyl)amino,bis(methylsulphonyl)amino, N-(carboxy ethyl)-N-(methyl)amino,carboxycyclopentylamino, carboxycyclopropylmethylamino, formyl, acetyl,acetoxyisopropyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl,ethoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl,methoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl,morpholinylethoxycarbonyl, ethoxycarbonylmethylidenyl,methylsulphonylaminocarbonyl, acetylaminosulphonyl,methoxyaminocarbonyl, tetrazolyl, tetrazolylmethyl, hydroxyoxadiazolyl,aminocarbonyl, aminosulphonyl, methylsulphoximinyl and(methyl)(N-methyl)sulphoximinyl.

Suitable examples of particular substituents on R¹ include one, two orthree substituents independently selected from hydroxyisopropyl andmethylsulphonyl.

In a particular embodiment, R¹ is substituted by hydroxy(C₁₋₆)alkyl. Inone aspect of that embodiment, R¹ is substituted by hydroxyisopropyl,especially 2-hydroxyprop-2-yl.

Selected values of R¹ include hydrogen, bromo, iodo, —CO₂R^(d),methoxycarbonylethyl, ethoxycarbonylethyl, hydroxybutynyl, chlorophenyl,hydroxyphenyl, pentafluoro-thiophenyl, methylsulphonylphenyl,aminomethylphenyl, aminoisopropylphenyl, acetyl-aminomethylphenyl,acetylphenyl, methoxycarbonylphenyl, aminocarbonylphenyl,aminosulphonylphenyl, acetylaminosulphonylphenyl,(methoxycarbonyl)(methyl)-pyrrolidinyl, oxopiperidinyl,ethoxycarbonylpiperidinyl, methylsulphonylpiperazinyl, morpholinyl,methylsulphonyl-1,2,3,6-tetrahydropyridinyl,acetyl-1,2,3,6-tetrahydropyridinyl,tert-butoxycarbonyl-1,2,3,6-tetrahydropyridinyl,methoxycarbonylmethyl-1,2,3,6-tetrahydropyridinyl, benzofuryl, thienyl,indolyl, pyrazolyl, methylpyrazolyl, dimethylpyrazolyl,(methyl)[N-methyl-N-(methylsulfonyl)amino]pyrazolyl, methylindazolyl,dimethylisoxazolyl, hydroxyisopropylthiazolyl, methylimidazolyl,dimethylimidazolyl, pyridinyl, fluoropyridinyl, cyanopyridinyl,methylpyridinyl, (cyano)-(methyl)pyridinyl, dimethylpyridinyl,trifluoromethylpyridinyl, ethenylpyridinyl, hydroxyisopropylpyridinyl,methoxypyridinyl, (methoxy)(methyl)pyridinyl, isopropoxy-pyridinyl,trifluoroethoxypyridinyl, (methyl)(trifluoroethoxy)pyridinyl,methylsulphonyl-pyridinyl, oxopyridinyl, (methyl)(oxo)pyridinyl,(dimethyl)(oxo)pyridinyl, aminopyridinyl, methylaminopyridinyl,dimethylaminopyridinyl, methoxyethylaminopyridinyl,N-(hydroxyethyl)-N-(methyl)aminopyridinyl,methylsulphonylaminopyridinyl, [bis(methylsulphonyl)amino]pyridinyl,carboxypyridinyl, quinolinyl, hydroxypyridazinyl, pyrimidinyl,fluoroisopropylpyrimidinyl, difluoroethylpyrimidinyl,hydroxyisopropylpyrimidinyl, methoxypyrimidinyl,carboxycyclobutyloxypyrimidinyl, methylthio-pyrimidinyl,methylsulphonylpyrimidinyl, oxopyrimidinyl, aminopyrimidinyl,dimethyl-aminopyrimidinyl, methoxyethylaminopyrimidinyl,N-(carboxyethyl)-N-(methyl)aminopyrimidinyl,carboxycyclopentylaminopyrimidinyl,carboxycyclopropylmethylamino-pyrimidinyl, acetoxyisopropylpyrimidinyl,ethoxycarbonylethylpyrimidinyl, hydroxypyrazinyl,hydroxyisopropylpyrazinyl, pyrrolidinylmethylphenyl,piperazinylmethylphenyl, pyridinylpiperazinyl,carboxycyclohexylpyrazolyl, carboxycyclohexyl-pyridinyl,fluoromethylcyclopropylpyrimidinyl, hydroxycyclopropylpyrimidinyl,acetyl-aminomethylcyclopropylpyrimidinyl, hydroxycyclobutylpyrimidinyl,(difluoro)-(hydroxy)cyclobutylpyrimidinyl,carboxycyclopentylpyrimidinyl, carboxycyclohexyl-pyrimidinyl,(carboxy)(methyl)cyclohexylpyrimidinyl,(carboxy)(hydroxy)cyclohexylpyrimidinyl,carboxymethylcyclohexylpyrimidinyl,ethoxycarbonylcyclohexyl-pyrimidinyl,(methoxycarbonyl)(methyl)cyclohexylpyrimidinyl,(ethoxycarbonyl)-(methyl)cyclohexylpyrimidinyl,carboxycyclohexylpyrazinyl, carboxycyclohexylmethyl-pyrimidinyl,carboxycyclohexenylpyridinyl, carboxycyclohexenylpyrimidinyl,ethoxycarbonylcyclohexenylpyrimidinyl,carboxybicyclo[3.1.0]hexanylpyridinyl,carboxybicyclo[3.1.0]hexanylpyrimidinyl,ethoxycarbonylbicyclo[3.1.0]hexanylpyrimidinyl,carboxybicyclo[4.1.0]heptanylpyrimidinyl,carboxybicyclo[2.2.2]octanylpyrimidinyl, pyrrolidinylpyridinyl,hydroxypyrrolidinylpyridinyl, hydroxytetrahydropyranylpyridinyl,piperidinylpyridinyl, acetylpiperidinylpyridinyl,(carboxy)(methyl)piperidinylpyridinyl,[(carboxy)(methyl)piperidinyl](fluoro)pyridinyl,Rcarboxy)(methyl)piperidinylKchloro)pyridinyl, piperazinylpyridinyl,(methyl)-(piperazinyl)pyridinyl, cyanoethylpiperazinylpyridinyl,trifluoroethylpiperazinylpyridinyl, methylsulphonylpiperazinylpyridinyl,methylsulphonylethylpiperazinylpyridinyl, oxopiperazinylpyridinyl,acetylpiperazinylpyridinyl,(tert-butoxycarbonylpiperazinyl)-(methyl)pyridinyl,carboxymethylpiperazinylpyridinyl, carboxyethylpiperazinylpyridinyl,ethoxycarbonylmethylpiperazinylpyridinyl,ethoxycarbonylethylpiperazinylpyridinyl, morpholinylpyridinyl,thiomorpholinylpyridinyl, oxothiomorpholinylpyridinyl,dioxothiomorpholinylpyridinyl, oxodiazepanylpyridinyl,fluorooxetanylpyrimidinyl, hydroxyoxetanylpyrimidinyl,difluoroazetidinylpyrimidinyl, hydroxyazetidinyl-pyrimidinyl,(hydroxy)(methyl)azetidinylpyrimidinyl,(hydroxy)(trifluoromethyl)-azetidinylpyrimidinyl,carboxyazetidinylpyrimidinyl,(tert-butoxycarbonyl)(hydroxy)-azetidinylpyrimidinyl,tetrazolylazetidinylpyrimidinyl, hydroxytetrahydrofuranyl-pyrimidinyl,hydroxypyrrolidinylpyrimidinyl, carboxypyrrolidinylpyrimidinyl,(carboxy)-(methyl)pyrrolidinylpyrimidinyl,carboxymethylpyrrolidinylpyrimidinyl,ethoxycarbonyl-pyrrolidinylpyrimidinyl,fluorotetrahydropyranylpyrimidinyl,hydroxytetrahydropyranyl-pyrimidinyl, difluoropiperidinylpyrimidinyl,(cyano)(methyl)piperidinylpyrimidinyl,(hydroxy)(nitromethyl)piperidinylpyrimidinyl,(hydroxy)(methyl)piperidinylpyrimidinyl,(hydroxy)(trifluoromethyl)piperidinylpyrimidinyl,(hydroxymethyl)(methyl)piperidinylpyrimidinyl,methylsulphonylpiperidinylpyrimidinyl, oxopiperidinylpyrimidinyl,(formyl)(methyl)piperidinylpyrimidinyl, carboxypiperidinylpyrimidinyl,(carboxy)-(fluoro)piperidinylpyrimidinyl,(carboxy)(methyl)piperidinylpyrimidinyl,(carboxy)-(ethyl)piperidinylpyrimidinyl,(carboxy)(trifluoromethyl)piperidinylpyrimidinyl,(carboxy)(hydroxy)piperidinylpyrimidinyl,(carboxy)(hydroxymethyl)piperidinylpyrimidinyl,(carboxy)(methoxy)piperidinylpyrimidinyl,(amino)(carboxy)piperidinylpyrimidinyl,carboxymethylpiperidinylpyrimidinyl,methoxycarbonylpiperidinyl-pyrimidinyl,ethoxycarbonylpiperidinylpyrimidinyl,(ethoxycarbonyl)(fluoro)piperidinylpyrimidinyl,(methoxycarbonyl)(methyl)piperidinylpyrimidinyl,(ethyl)(methoxy-carbonyl)piperidinylpyrimidinyl,(isopropyl)(methoxycarbonyl)piperidinylpyrimidinyl,(ethoxycarbonyl)(methyl)piperidinylpyrimidinyl,(n-butoxycarbonyl)(methyl)piperidinylpyrimidinyl,(ethoxycarbonyl)(trifluoromethyl)piperidinylpyrimidinyl,(ethoxycarbonyl)-(hydroxymethyl)piperidinylpyrimidinyl,(methoxy)(methoxycarbonyl)piperidinylpyrimidinyl,(carboxy)(methoxycarbonyl)piperidinylpyrimidinyl,(methyl)-(morpholinylethoxycarbonyl)piperidinylpyrimidinyl,ethoxycarbonylmethylpiperidinyl-pyrimidinyl,methylsulphonylaminocarbonylpiperidinylpyrimidinyl,acetylamino-sulphonylpiperidinylpyrimidinyl,methoxyaminocarbonylpiperidinylpyrimidinyl,tetrazolylpiperidinylpyrimidinyl,hydroxyoxadiazolylpiperidinylpyrimidinyl,amino-sulphonylpiperidinylpyrimidinyl, piperazinylpyrimidinyl,methylsulphonylpiperazinyl-pyrimidinyl, oxopiperazinylpyrimidinyl,carboxypiperazinylpyrimidinyl, carboxyethyl-piperazinylpyrimidinyl,tert-butoxycarbonylpiperazinylpyrimidinyl,tetrazolylmethyl-piperazinylpyrimidinyl,trioxohexahydro-[1,2,5]thiadiazolo[2,3-c]pyrazinylpyrimidinyl,morpholinylpyrimidinyl, dimethylmorpholinylpyrimidinyl,hydroxymethylmorpholinyl-pyrimidinyl, carboxymorpholinylpyrimidinyl,(carboxy)(methyl)morpholinylpyrimidinyl,carboxymethylmorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl,dioxo-thiomorpholinylpyrimidinyl, carboxyazepanylpyrimidinyl,carboxyoxazepanyl-pyrimidinyl, oxodiazepanylpyrimidinyl,(oxodiazepanyl)(trifluoromethyl)pyrimidinyl,(oxodiazepanyl)(methoxy)pyrimidinyl, (methyl)(oxo)diazepanylpyrimidinyl,dioxo-thiadiazepanylpyrimidinyl, hydroxyoxetanylpyrazinyl,(carboxy)(methyl)piperidinylpyrazinyl,(ethoxycarbonyl)(methyl)piperidinylpyrazinyl, morpholinylmethylthienyl,morpholinylethylpyrazolyl, carboxy-3-azabicyclo[3.1.0]hexanylpyridinyl,carboxy-3-azabicyclo[3.1.0]hexanylpyridazinyl,carboxy-3-azabicyclo[3.1.0]hexanylpyrimidinyl,(carboxy)(methyl)-3-azabicyclo[3.1.0]hexanylpyrimidinyl,methoxycarbonyl-3-azabicyclo[3.1.0]hexanylpyrimidinyl,ethoxycarbonyl-3-azabicyclo[3.1.0]hexanylpyrimidinyl,2-oxa-5-azabicyclo[2.2.1]heptanylpyrimidinyl,carboxy-2-oxa-5-azabicyclo-[2.2.1]heptanylpyrimidinyl,carboxy-3-azabicyclo[3.1.1]heptanylpyrimidinyl,6-oxa-3-azabicyclo[3.1.1]heptanylpyrimidinyl,carboxy-3-azabicyclo[4.1.0]heptanylpyridinyl,carboxy-3-azabicyclo[4.1.0]heptanylpyrimidinyl,methoxycarbonyl-3-azabicyclo[4.1.0]-heptanylpyrimidinyl,ethoxycarbonyl-3-azabicyclo[4.1.0]heptanylpyrimidinyl,(hydroxy)-(methyl)(oxo)-2-oxabicyclo[2.2.2]octanylpyrimidinyl,carboxy-3-azabicyclo[3.2.1]-octanylpyrimidinyl,methoxycarbonyl-3-azabicyclo[3.2.1]octanylpyrimidinyl,oxo-8-azabicyclo[3.2.1]octanylpyrimidinyl,ethoxycarbonylmethylidenyl-8-azabicyclo[3.2.1]-octanylpyrimidinyl,3-oxa-8-azabicyclo[3.2.1]octanylpyrimidinyl,oxo-3,6-diazabicyclo-[3.2.2]nonanylpyrimidinyl,carboxy-3-oxa-7-azabicyclo[3.3.1]nonanylpyrimidinyl,3,7-dioxa-9-azabicyclo[3.3.1]nonanylpyrimidinyl,carboxy-5-azaspiro[2.3]hexanylpyrimidinyl,(carboxy)(methyl)-5-azaspiro[2.3]hexanylpyrimidinyl,carboxy-5-azaspiro-[2.4]heptanylpyrimidinyl,carboxy-2-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro-[3.3]heptanylpyrimidinyl,3-oxa-6-azaspiro[3.3]heptanylpyrimidinyl,dioxo-6-thia-2-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro[3.4]octanylpyrimidinyl,2-oxa-6-azaspiro[3.5]nonanylpyrimidinyl,2-oxa-7-azaspiro[3.5]nonanylpyrimidinyl and(dioxo)(methyl)-2,4,8-triazaspiro[4.5]decanylpyrimidinyl.

Illustrative values of R¹ include hydrogen, methylsulphonylphenyl andhydroxyisopropylpyrimidinyl.

Typically, R² represents hydrogen, halogen, trifluoromethyl or —OR^(a);or R² represents optionally substituted C₁₋₆ alkyl.

Suitably, R² represents hydrogen or halogen.

Typical examples of optional substituents on R² include C₂₋₆alkoxycarbonyl.

Typical examples of particular substituents on R² includeethoxycarbonyl.

In a first embodiment, R² represents hydrogen. In a second embodiment,R² represents halogen. In one aspect of that embodiment, R² representsfluoro. In another aspect of that embodiment, R² represents chloro. In athird embodiment, R² represents trifluoromethyl. In a fourth embodiment,R² represents —OR^(a). In a fifth embodiment, R² represents optionallysubstituted C₁₋₆ alkyl. In one aspect of that embodiment, R² representsunsubstituted methyl. In another aspect of that embodiment, R²represents unsubstituted ethyl. In a further aspect of that embodiment,R² represents monosubstituted methyl or monosubstituted ethyl.

Typical values of R² include hydrogen, fluoro, chloro, trifluoromethyl,—OR^(a), methyl and ethoxycarbonylethyl.

Suitable values of R² include hydrogen and fluoro.

Typically, R³ represents hydrogen, halogen or C₁₋₆ alkyl.

In a first embodiment, R³ represents hydrogen. In a second embodiment,R³ represents halogen. In one aspect of that embodiment, R³ representsfluoro. In a third embodiment, R³ represents C₁₋₆ alkyl. In one aspectof that embodiment, R³ represents methyl. In another aspect of thatembodiment, R³ represents ethyl.

In a particular embodiment, R⁴ represents hydrogen.

Suitably, R⁵ represents hydrogen or methyl.

In a first embodiment, R⁵ represents hydrogen. In a second embodiment,R⁵ represents C₁₋₆ alkyl, especially methyl.

Suitably, R⁶ represents hydrogen, methyl or ethyl.

In a first embodiment, R⁶ represents hydrogen. In a second embodiment,R⁶ represents C₁₋₆ alkyl, especially methyl or ethyl. In one aspect ofthat embodiment, R⁶ represents methyl. In another aspect of thatembodiment, R⁶ represents ethyl.

Typical examples of suitable substituents on R^(a), R^(b), R^(c), R^(d)or R^(e), or on the heterocyclic moiety —NR^(b)R^(c), include halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy, difluoromethoxy, trifluoromethoxy, C₁₋₆alkoxy(C₁₋₆)alkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl, C₁₋₆alkylsulphonyl, hydroxy, hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, cyano,trifluoromethyl, oxo, C₂₋₆ alkylcarbonyl, carboxy, C₂₋₆ alkoxycarbonyl,C₂₋₆ alkylcarbonyloxy, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,phenylamino, pyridinylamino, C₂₋₆ alkylcarbonylamino, C₂₋₆alkylcarbonylamino(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonylamino, C₁₋₆alkylsulphonylamino, aminocarbonyl, C₁₋₆ alkylaminocarbonyl anddi(C₁₋₆)alkylaminocarbonyl.

Typical examples of specific substituents on R^(a), R^(b), R^(c), R^(d)or R^(e), or on the heterocyclic moiety —NR^(b)R^(c), include fluoro,chloro, bromo, methyl, ethyl, isopropyl, methoxy, isopropoxy,difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio,methylsulphinyl, methylsulphonyl, hydroxy, hydroxymethyl, hydroxyethyl,aminomethyl, cyano, trifluoromethyl, oxo, acetyl, carboxy,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, acetoxy, amino,methylamino, ethylamino, dimethylamino, phenylamino, pyridinylamino,acetylamino, tert-butoxycarbonylamino, acetylaminomethyl,methylsulphonylamino, aminocarbonyl, methylaminocarbonyl anddimethylaminocarbonyl.

Suitably, R^(a) represents C₁₋₆ alkyl, aryl(C₁₋₆)alkyl orheteroaryl(C₁₋₆)alkyl, any of which groups may be optionally substitutedby one or more substituents.

Selected values of R^(a) include methyl, ethyl, benzyl andisoindolylpropyl, any of which groups may be optionally substituted byone or more substituents.

Selected examples of suitable substituents on R^(a) include C₁₋₆ alkoxyand oxo.

Selected examples of specific substituents on R^(a) include methoxy andoxo.

In one embodiment, R^(a) represents optionally substituted C₁₋₆ alkyl.In one aspect of that embodiment, R^(a) ideally represents unsubstitutedC₁₋₆ alkyl, especially methyl. In another aspect of that embodiment,R^(a) ideally represents substituted C₁₋₆ alkyl, e.g. methoxyethyl. Inanother embodiment, R^(a) represents optionally substituted aryl. In oneaspect of that embodiment, R^(a) represents unsubstituted aryl,especially phenyl. In another aspect of that embodiment, R^(a)represents monosubstituted aryl, especially methylphenyl. In anotherembodiment, R^(a) represents optionally substituted aryl(C₁₋₆)alkyl,ideally unsubstituted aryl(C₁₋₆)alkyl, especially benzyl. In a furtherembodiment, R^(a) represents optionally substituted heteroaryl. In afurther embodiment, R^(a) represents optionally substitutedheteroaryl(C₁₋₆)alkyl, e.g. dioxoisoindolylpropyl.

Specific values of R^(a) include methyl, methoxyethyl, benzyl anddioxoisoindolylpropyl.

In a particular aspect, R^(b) represents hydrogen or trifluoromethyl; orC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, aryl,aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any ofwhich groups may be optionally substituted by one or more substituents.

Selected values of R^(b) include hydrogen; or C₁₋₆ alkyl,aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl or C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, any of which groups may be optionallysubstituted by one or more substituents.

Typical values of R^(b) include hydrogen and C₁₋₆ alkyl.

Illustratively, R^(b) represents hydrogen or trifluoromethyl; or methyl,ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, pentyl,hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, phenyl, benzyl, phenylethyl, azetidinyl,tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, piperidinyl,homopiperidinyl, morpholinyl, azetidinylmethyl, tetrahydrofurylmethyl,pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl,thiazolidinylmethyl, imidazolidinylethyl, piperidinylmethyl,piperidinylethyl, tetrahydroquinolinylmethyl, piperazinylpropyl,morpholinylmethyl, morpholinylethyl, morpholinylpropyl, pyridinyl,indolylmethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl,imidazolylethyl, benzimidazolylmethyl, triazolylmethyl, pyridinylmethylor pyridinylethyl, any of which groups may be optionally substituted byone or more substituents.

Representative values of R^(b) include hydrogen; or methyl, ethyl,n-propyl, benzyl, pyrrolidinyl or morpholinylpropyl, any of which groupsmay be optionally substituted by one or more substituents.

Selected examples of suitable substituents on R^(b) include C₁₋₆ alkoxy,C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl, C₁₋₆ alkylsulphonyl, hydroxy,cyano, C₂₋₆ alkoxycarbonyl, di-(C₁₋₆)alkylamino and C₂₋₆alkoxycarbonylamino.

Selected examples of specific substituents on R^(b) include methoxy,methylthio, methylsulphinyl, methylsulphonyl, hydroxy, cyano,tert-butoxycarbonyl, dimethylamino and tert-butoxycarbonylamino.

Specific values of R^(b) include hydrogen, methyl, methoxyethyl,methylthioethyl, methylsulphinylethyl, methylsulphonylethyl,hydroxyethyl, cyanoethyl, dimethylaminoethyl,tert-butoxycarbonylaminoethyl, dihydroxypropyl, benzyl, pyrrolidinyl,tert-butoxycarbonylpyrrolidinyl and morpholinylpropyl.

In one embodiment, R^(b) represents hydrogen. In another embodiment,R^(b) represents C₁₋₆ alkyl, especially methyl.

Selected values of R^(c) include hydrogen; or C₁₋₆ alkyl, C₃₋₇cycloalkyl or C₃₋₇ heterocycloalkyl, any of which groups may beoptionally substituted by one or more substituents.

In a particular aspect, R^(c) represents hydrogen, C₁₋₆ alkyl or C₃₋₇cycloalkyl.

Representative values of R^(c) include hydrogen; or methyl, cyclobutyl,cyclopentyl, cyclohexyl, tetrahydropyranyl and piperidinyl, any of whichgroups may be optionally substituted by one or more substituents.

Selected examples of suitable substituents on R^(c) include C₂₋₆alkylcarbonyl and C₂₋₆ alkoxycarbonyl.

Selected examples of specific substituents on R^(c) include acetyl andtert-butoxycarbonyl.

Specific values of R^(c) include hydrogen, methyl, cyclobutyl,cyclopentyl, cyclohexyl, tetrahydropyranyl, acetylpiperidinyl andtert-butoxycarbonylpiperidinyl,

Suitably, R^(c) represents hydrogen or C₁₋₆ alkyl. In one embodiment,R^(c) is hydrogen. In another embodiment, R^(c) represents C₁₋₆ alkyl,especially methyl or ethyl, particularly methyl. In a furtherembodiment, R^(c) represents C₃₋₇ cycloalkyl, e.g. cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl.

Alternatively, the moiety —NR^(b)R^(c) may suitably representazetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl,thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl,thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl,homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may beoptionally substituted by one or more substituents.

Selected examples of suitable substituents on the heterocyclic moiety—NR^(b)R^(c) include C₁₋₆ alkyl, C₁₋₆ alkylsulphonyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, cyano, oxo, C₂₋₆ alkylcarbonyl,carboxy, C₂₋₆ alkoxycarbonyl, amino, C₂₋₆ alkylcarbonylamino, C₂₋₆alkylcarbonylamino(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonylamino, C₁₋₆alkylsulphonylamino and aminocarbonyl.

Selected examples of specific substituents on the heterocyclic moiety—NR^(b)R^(c) include methyl, methylsulphonyl, hydroxy, hydroxymethyl,aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino,acetylamino, acetylaminomethyl, tert-butoxycarbonylamino,methylsulphonylamino and aminocarbonyl.

Specific values of the moiety —NR^(b)R^(c) include azetidin-1-yl,hydroxyazetidin-1-yl, hydroxymethylazetidin-1-yl,(hydroxy)(hydroxymethyl)azetidin-1-yl, aminomethyl-azetidin-1-yl,cyanoazetidin-1-yl, carboxyazetidin-1-yl, aminoazetidin-1-yl,aminocarbonylazetidin-1-yl, pyrrolidin-1-yl, aminomethylpyrrolidin-1-yl,oxopyrrolidin-1-yl, acetylaminomethylpyrrolidin-1-yl,tert-butoxycarbonylaminopyrrolidin-1-yl, oxooxazolidin-3-yl,hydroxyisoxazolidin-2-yl, thiazolidin-3-yl, oxothiazolidin-3-yl,dioxo-isothiazolidin-2-yl, piperidin-1-yl, hydroxypiperidin-1-yl,hydroxymethylpiperidin-1-yl, aminopiperidin-1-yl,acetylaminopiperidin-1-yl, tert-butoxycarbonylaminopiperidin-1-yl,methylsulphonylaminopiperidin-1-yl, morpholin-4-yl, piperazin-1-yl,methylpiperazin-1-yl, methylsulphonylpiperazin-1-yl, oxopiperazin-1-yl,acetylpiperazin-1-yl, ethoxycarbonylpiperazin-1-yl andoxohomopiperazin-1-yl.

Suitably, R^(d) represents hydrogen; or C₁₋₆ alkyl, aryl or heteroaryl,any of which groups may be optionally substituted by one or moresubstituents.

Selected examples of suitable values for R^(d) include hydrogen, methyl,ethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl,phenyl, thiazolidinyl, thienyl, imidazolyl and thiazolyl, any of whichgroups may be optionally substituted by one or more substituents.

Selected examples of suitable substituents on R^(d) include halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy, oxo, C₂₋₆ alkylcarbonyloxy anddi(C₁₋₆)alkylamino.

Selected examples of particular substituents on R^(d) include fluoro,methyl, methoxy, oxo, acetoxy and dimethylamino.

In one embodiment, R^(d) represents hydrogen. In another embodiment,R^(d) represents optionally substituted C₁₋₆ alkyl. In one aspect ofthat embodiment, R^(d) ideally represents unsubstituted C₁₋₆ alkyl, e.g.methyl, ethyl, isopropyl, 2-methylpropyl or tert-butyl, especiallymethyl. In another aspect of that embodiment, R^(d) ideally representssubstituted C₁₋₆ alkyl, e.g. substituted methyl or substituted ethyl,including acetoxymethyl, dimethylaminomethyl and trifluoroethyl. Inanother embodiment, R^(d) represents optionally substituted aryl. In oneaspect of that embodiment, R^(d) represents unsubstituted aryl,especially phenyl. In another aspect of that embodiment, R^(d)represents monosubstituted aryl, especially methylphenyl. In a furtheraspect of that embodiment, R^(d) represents disubstituted aryl, e.g.dimethoxyphenyl. In a further embodiment, R^(d) represents optionallysubstituted heteroaryl, e.g. thienyl, chlorothienyl, methylthienyl,methylimidazolyl or thiazolyl. In another embodiment, R^(d) representsoptionally substituted C₃₋₇ cycloalkyl, e.g. cyclopropyl or cyclobutyl.In a further embodiment, R^(d) represents optionally substituted C₃₋₇heterocycloalkyl, e.g. thiazolidinyl or oxothiazolidinyl.

Selected examples of specific values for R^(d) include hydrogen, methyl,acetoxymethyl, dimethylaminomethyl, ethyl, trifluoroethyl, isopropyl,2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl,dimethoxyphenyl, thiazolidinyl, oxothiazolidinyl, thienyl,chlorothienyl, methylthienyl, methylimidazolyl and thiazolyl.

Suitably, R^(e) represents C₁₋₆ alkyl or aryl, either of which groupsmay be optionally substituted by one or more substituents.

Selected examples of suitable substituents on R^(e) include C₁₋₆ alkyl,especially methyl.

In one embodiment, R^(e) represents optionally substituted C₁₋₆ alkyl,ideally unsubstituted C₁₋₆ alkyl, e.g. methyl or propyl, especiallymethyl. In another embodiment, R^(e) represents optionally substitutedaryl. In one aspect of that embodiment, R^(e) represents unsubstitutedaryl, especially phenyl. In another aspect of that embodiment, R^(e)represents monosubstituted aryl, especially methylphenyl. In a furtherembodiment, R^(e) represents optionally substituted heteroaryl.

Selected values of R^(e) include methyl, propyl and methylphenyl.

One sub-class of compounds according to the invention is represented bythe compounds of formula (IIA) and N-oxides thereof, andpharmaceutically acceptable salts and solvates thereof, and glucuronidederivatives thereof, and co-crystals thereof:

wherein

R¹¹ represents halogen or cyano; or R¹¹ represents C₁₋₆ alkyl, C₂₋₆alkynyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl,heteroaryl, (C₃₋₇)heterocycloalkyl-(C₁₋₆)alkyl-aryl-,heteroaryl(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl(C₁₋₆)alkyl-hetero aryl-,(C₄₋₇)cycloalkenyl-heteroaryl-, (C₄₋₉)bicycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl-hetero aryl-,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents;

R¹⁵ and R¹⁶ independently represent hydrogen, halogen, cyano, nitro,C₁₋₆ alkyl, trifluoromethyl, hydroxy, C₁₋₆ alkoxy, difluoromethoxy,trifluoromethoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, arylamino,C₂₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, formyl, C₂₋₆alkylcarbonyl, C₃₋₆ cycloalkylcarbonyl, C₃₋₆ heterocycloalkylcarbonyl,carboxy, C₂₋₆ alkoxycarbonyl, aminocarbonyl, C₁₋₆ alkylaminocarbonyl,di(C₁₋₆)alkylaminocarbonyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl ordi(C₁₋₆)alkylaminosulfonyl; and

q, A, G, E, Q and Z are as defined above.

Examples of optional substituents which may be present on R¹¹ includeone, two or three substituents independently selected from halogen,halo(C₁₋₆)alkyl, cyano, cyano(C₁₋₆)alkyl, nitro, nitro(C₁₋₆)alkyl, C₁₋₆alkyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl,C₂₋₆ alkenyl, hydroxy, hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, difluoromethoxy,trifluoromethoxy, trifluoroethoxy, carboxy(C₃₋₇)cycloalkyloxy, C₁₋₃alkylenedioxy, C₁₋₆ alkoxy(C₁₋₆)alkyl, pentafluorothio, C₁₋₆ alkylthio,C₁₋₆ alkylsulphinyl, C₁₋₆ alkylsulphonyl,(C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, oxo, amino, amino(C₁₋₆)alkyl, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, hydroxy(C₁₋₆)alkylamino, C₁₋₆alkoxyamino, (C₁₋₆)alkoxy-(C₁₋₆)alkyl amino,[(C₁₋₆)alkoxy](hydroxy)(C₁₋₆)alkylamino,[(C₁₋₆)alkylthio](hydroxy)-(C₁₋₆)alkylamino,N—[(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino,di(C₁₋₆)alkylamino(C₁₋₆)-alkylamino,N-[di(C₁₋₆)alkylamino(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino,hydroxy-(C₁-C₆)alkyl(C₃₋₇)cycloalkylamino,(hydroxy)[(C₃₋₇)cycloalkyl(C₁₋₆)alkyl]amino,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkylamino,oxo(C₃₋₇)heterocycloalkyl(C₁₋₆)alkylamino, (C₁₋₆)alkylheteroarylamino,heteroaryl(C₁₋₆)alkylamino, (C₁₋₆)alkylheteroaryl(C₁₋₆)alkylamino, C₂₋₆alkylcarbonylamino, N—[(C₁₋₆)alkyl]-N—[(C₂₋₆)alkylcarbonyl]amino,(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, C₃₋₆ alkenylcarbonylamino,bis[(C₃₋₆)alkenylcarbonyl]amino,N—[(C₁₋₆)alkyl]-N—[(C₃₋₇)cycloalkylcarbonyl]amino, C₂₋₆alkoxycarbonylamino, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkylamino, C₁₋₆alkylaminocarbonylamino, C₁₋₆ alkylsulphonylamino,N—[(C₁₋₆)alkyl]-N—[(C₁₋₆)alkylsulphonyl]amino,bis[(C₁₋₆)alkylsulphonyl]amino,N—[(C₁-C₆)alkyl]-N-[carboxy(C₁₋₆)alkyl]amino,carboxy(C₃₋₇)cycloalkylamino, carboxy-(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,formyl, C₂₋₆ alkylcarbonyl, (C₃₋₇)cycloalkylcarbonyl, phenylcarbonyl,(C₂₋₆)alkylcarbonyloxy(C₁₋₆)alkyl, carboxy, carboxy(C₁₋₆)alkyl, C₂₋₆alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonylmethylidenyl, acarboxylic acid isostere or prodrug moiety Ω as defined herein,—(C₁₋₆)alkyl-Ω, aminocarbonyl, C₁₋₆ alkylaminocarbonyl,hydroxy(C₁₋₆)alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl,aminocarbonyl(C₁₋₆)alkyl, aminosulphonyl, di(C₁₋₆)alkylaminosulphonyl,(C₁₋₆)alkylsulphoximinyl and [(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]-sulphoximinyl.

Examples of particular substituents on R¹¹ include fluoro, chloro,bromo, fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitro,nitromethyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethenyl,hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy,difluoromethoxy, trifluoromethoxy, trifluoroethoxy,carboxycyclobutyloxy, methylenedioxy, ethylenedioxy, methoxymethyl,methoxyethyl, pentafluorothio, methylthio, methylsulphinyl,methylsulphonyl, methylsulphonylethyl, oxo, amino, aminomethyl,aminoisopropyl, methylamino, ethylamino, dimethylamino,hydroxyethylamino, hydroxypropylamino, (hydroxy)(methyl)propylamino,methoxyamino, methoxyethylamino, (hydroxy)(methoxy)(methyl)propylamino,(hydroxy)(methylthio)butylamino, N-(hydroxyethyl)-N-(methyl)amino,dimethylaminoethylamino, (dimethylamino)(methyl)-propylamino,N-(dimethylaminoethyl)-N-(hydroxyethyl)amino,hydroxymethyl-cyclopentylamino, hydroxycyclobutylmethylamino,(cyclopropyl)(hydroxy)propylamino, morpholinylethylamino,oxopyrrolidinylmethylamino, ethyloxadiazolylamino,methyl-thiadiazolylamino, thiazolylmethylamino, thiazolylethylamino,pyrimidinylmethylamino, methylpyrazolylmethylamino, acetylamino,N-acetyl-N-methylamino, N-isopropyl-carbonyl-N-methylamino,acetylaminomethyl, ethenylcarbonylamino, bis(ethenyl-carbonyl)amino,N-cyclopropylcarbonyl-N-methylamino, methoxycarbonylamino,ethoxycarbonylamino, tert-butoxycarbonylamino,methoxycarbonylethylamino, ethylaminocarbonylamino,butylaminocarbonylamino, methylsulphonylamino,N-methyl-N-(methylsulphonyl)amino, bis(methylsulphonyl)amino,N-(carboxymethyl)-N-methylamino, N-(carboxyethyl)-N-methylamino,carboxycyclopentylamino, carboxycyclopropylmethylamino, formyl, acetyl,isopropylcarbonyl, cyclobutylcarbonyl, phenylcarbonyl, acetoxyisopropyl,carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl,n-butoxycarbonyl, tert-butoxycarbonyl, methoxycarbonylmethyl,ethoxycarbonylmethyl, ethoxycarbonylethyl, morpholinylethoxycarbonyl,ethoxycarbonylmethylidenyl, methylsulphonylaminocarbonyl,acetylaminosulphonyl, methoxyaminocarbonyl, tetrazolyl,tetrazolylmethyl, hydroxyoxadiazolyl, aminocarbonyl,methylamino-carbonyl, hydroxyethylaminocarbonyl, dimethylaminocarbonyl,aminocarbonylmethyl, aminosulphonyl, methylaminosulphonyl,dimethylaminosulphonyl, methylsulphoximinyl and(methyl)(N-methyl)sulphoximinyl.

Generally, R¹¹ represents C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl, C₃₋₇heterocycloalkyl, C₃₋₇ heterocycloalkenyl, heteroaryl,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-,heteroaryl-(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl(C₁₋₆)alkyl-heteroaryl-, (C₄₋₇)cycloalkenyl-heteroaryl-,(C₄₋₉) bicycloalkyl-heteroaryl-, (C₃₋₇)heterocycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-hetero aryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

More generally, R¹¹ represents halogen; or R¹¹ represents aryl, C₃₋₇heterocycloalkyl, heteroaryl, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl-heteroaryl-, (C₄₋₉)heterobicycloalkyl-heteroaryl-or (C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

Appositely, R¹¹ represents aryl or heteroaryl, either of which groupsmay be optionally substituted by one or more substituents.

In a first embodiment, R¹¹ represents halogen. In one aspect of thatembodiment, R¹¹ represents bromo. In one aspect of that embodiment, R¹¹represents iodo.

In a second embodiment, R¹¹ represents cyano.

In a third embodiment, R¹¹ represents optionally substituted C₁₋₆ alkyl.In one aspect of that embodiment, R¹¹ represents optionally substitutedethyl.

In a fourth embodiment, R¹¹ represents optionally substituted C₂₋₆alkynyl. In one aspect of that embodiment, R¹¹ represents optionallysubstituted butynyl.

In a fifth embodiment, R¹¹ represents optionally substituted aryl. Inone aspect of that embodiment, R¹¹ represents optionally substitutedphenyl.

In a sixth embodiment, R¹¹ represents optionally substituted C₃₋₇heterocycloalkyl.

In a seventh embodiment, R¹¹ represents optionally substituted C₃₋₇heterocycloalkenyl.

In an eighth embodiment, R¹¹ represents optionally substitutedheteroaryl. In selected aspects of that embodiment, R¹¹ representsbenzofuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl,thiazolyl, imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinylor pyrazinyl, any of which groups may be optionally substituted by oneor more substituents.

In a ninth embodiment, R¹¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl(C₁₋₆)alkyl-aryl-. In a first aspect of thatembodiment, R¹¹ represents optionally substitutedpyrrolidinylmethylphenyl-. In a second aspect of that embodiment, R¹¹represents optionally substituted piperazinylmethylphenyl-.

In a tenth embodiment, R¹¹ represents optionally substitutedheteroaryl(C₃₋₇)-heterocycloalkyl-. In one aspect of that embodiment,R¹¹ represents optionally substituted pyridinylpiperazinyl-.

In an eleventh embodiment, R¹¹ represents optionally substituted(C₃₋₇)cycloalkyl-heteroaryl-. In a first aspect of that embodiment, R¹¹represents optionally substituted cyclohexylpyrazolyl-. In a secondaspect of that embodiment, R¹¹ represents optionally substitutedcyclohexylpyridinyl-. In a third aspect of that embodiment, R¹¹represents optionally substituted cyclopropylpyrimidinyl-. In a fourthaspect of that embodiment, R¹¹ represents optionally substitutedcyclobutylpyrimidinyl-. In a fifth aspect of that embodiment, R¹¹represents optionally substituted cyclopentylpyrimidinyl-. In a sixthaspect of that embodiment, R¹¹ represents optionally substitutedcyclohexylpyrimidinyl-. In a seventh aspect of that embodiment, R¹¹represents optionally substituted cyclohexylpyrazinyl-.

In a twelfth embodiment, R¹¹ represents optionally substituted(C₄₋₇)cycloalkenyl-heteroaryl-.

In a thirteenth embodiment, R¹¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl-heteroaryl-. In a first aspect of thatembodiment, R¹¹ represents optionally substitutedpyrrolidinylpyridinyl-. In a second aspect of that embodiment, R¹¹optionally substituted tetrahydropyranylpyridinyl-. In a third aspect ofthat embodiment, R¹¹ represents optionally substitutedpiperidinylpyridinyl-. In a fourth aspect of that embodiment, R¹¹represents optionally substituted piperazinylpyridinyl-. In a fifthaspect of that embodiment, R¹¹ represents optionally substitutedmorpholinylpyridinyl-. In a sixth aspect of that embodiment, R¹¹represents optionally substituted thiomorpholinylpyridinyl-. In aseventh aspect of that embodiment, R¹¹ represents optionally substituteddiazepanylpyridinyl-. In an eighth aspect of that embodiment, R¹¹represents optionally substituted oxetanylpyrimidinyl-. In a ninthaspect of that embodiment, R¹¹ represents optionally substitutedazetidinylpyrimidinyl-. In a tenth aspect of that embodiment, R¹¹represents optionally substituted tetrahydrofuranylpyrimidinyl-. In aneleventh aspect of that embodiment, R¹¹ represents optionallysubstituted pyrrolidinylpyrimidinyl-. In a twelfth aspect of thatembodiment, R¹¹ represents optionally substitutedtetrahydropyranylpyrimidinyl-. In a thirteenth aspect of thatembodiment, R¹¹ represents optionally substitutedpiperidinylpyrimidinyl-. In a fourteenth aspect of that embodiment, R¹¹represents optionally substituted piperazinylpyrimidinyl-. In afifteenth aspect of that embodiment, R¹¹ represents optionallysubstituted morpholinylpyrimidinyl-. In a sixteenth aspect of thatembodiment, R¹¹ represents optionally substitutedthiomorpholinylpyrimidinyl-. In a seventeenth aspect of that embodiment,R¹¹ represents optionally substituted azepanylpyrimidinyl-. In aneighteenth aspect of that embodiment, R¹¹ represents optionallysubstituted oxazepanylpyrimidinyl-. In a nineteenth aspect of thatembodiment, R¹¹ represents optionally substituteddiazepanylpyrimidinyl-. In a twentieth aspect of that embodiment, R¹¹represents optionally substituted thiadiazepanylpyrimidinyl-. In atwenty-first aspect of that embodiment, R¹¹ represents optionallysubstituted oxetanylpyrazinyl-. In a twenty-second aspect of thatembodiment, R¹¹ represents optionally substituted piperidinylpyrazinyl-.

In a fourteenth embodiment, R¹¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-. In a first aspect ofthat embodiment, R¹¹ represents optionally substitutedmorpholinylmethylthienyl-. In a second aspect of that embodiment, R¹¹represents optionally substituted morpholinylethylpyrazolyl-.

In a fifteenth embodiment, R¹¹ represents optionally substituted(C₃₋₇)-heterocycloalkenyl-heteroaryl-.

In a sixteenth embodiment, R¹¹ represents optionally substituted(C₄₋₉)-heterobicycloalkyl-heteroaryl-.

In a seventeenth embodiment, R¹¹ represents optionally substituted(C₄₋₉)-spiroheterocycloalkyl-heteroaryl-.

In an eighteenth embodiment, R¹¹ represents optionally substituted(C₃₋₇)-cycloalkyl(C₁₋₆)alkyl-heteroaryl-. In one aspect of thatembodiment, R¹¹ represents optionally substitutedcyclohexylmethylpyrimidinyl-.

In a nineteenth embodiment, R¹¹ represents optionally substituted(C₄₋₉)-bicycloalkyl-heteroaryl-.

Appositely, R¹¹ represents bromo or iodo; or R¹¹ represents ethyl,butynyl, phenyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,1,2,3,6-tetrahydropyridinyl, benzofuryl, thienyl, indolyl, pyrazolyl,indazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, quinolinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethylphenyl,piperazinylmethylphenyl, pyridinylpiperazinyl, cyclohexylpyrazolyl,cyclohexylpyridinyl, cyclopropylpyrimidinyl, cyclobutylpyrimidinyl,cyclopentylpyrimidinyl, cyclohexylpyrimidinyl, cyclohexylpyrazinyl,cyclohexylmethylpyrimidinyl, cyclohexenylpyridinyl,cyclohexenylpyrimidinyl, bicyclo[3.1.0]hexanylpyridinyl,bicyclo[3.1.0]hexanylpyrimidinyl, bicyclo[4.1.0]heptanylpyrimidinyl,bicyclo[2.2.2]octanylpyrimidinyl, pyrrolidinylpyridinyl,tetrahydropyranylpyridinyl, piperidinylpyridinyl, piperazinylpyridinyl,morpholinylpyridinyl, thiomorpholinylpyridinyl, diazepanylpyridinyl,oxetanylpyrimidinyl, azetidinylpyrimidinyl,tetrahydrofuranylpyrimidinyl, pyrrolidinylpyrimidinyl,tetrahydropyranylpyrimidinyl, piperidinylpyrimidinyl,piperazinylpyrimidinyl,hexahydro-[1,2,5]thiadiazolo[2,3-c]pyrazinylpyrimidinyl,morpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, azepanylpyrimidinyl,oxazepanylpyrimidinyl, diazepanylpyrimidinyl, thiadiazepanylpyrimidinyl,oxetanylpyrazinyl, piperidinylpyrazinyl, morpholinylmethylthienyl,morpholinylethylpyrazolyl, 3-azabicyclo[3.1.0]-hexanylpyridinyl,3-azabicyclo[3.1.0]hexanylpyridazinyl,3-azabicyclo[3.1.0]hexanylpyrimidinyl,2-oxa-5-azabicyclo[2.2.1]heptanylpyrimidinyl,3-azabicyclo[3.1.1]heptanylpyrimidinyl,6-oxa-3-azabicyclo[3.1.1]heptanylpyrimidinyl,3-azabicyclo[4.1.0]heptanylpyridinyl,3-azabicyclo[4.1.0]heptanylpyrimidinyl,2-oxabicyclo[2.2.2]octanylpyrimidinyl,3-azabicyclo[3.2.1]octanylpyrimidinyl,8-azabicyclo[3.2.1]octanylpyrimidinyl,3-oxa-8-azabicyclo[3.2.1]octanylpyrimidinyl,3,6-diazabicyclo[3.2.2]-nonanylpyrimidinyl,3-oxa-7-azabicyclo[3.3.1]nonanylpyrimidinyl,3,7-dioxa-9-azabicyclo[3.3.1]nonanylpyrimidinyl,5-azaspiro[2.3]hexanylpyrimidinyl, 5-azaspiro-[2.4]heptanylpyrimidinyl,2-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro[3.3]-heptanylpyrimidinyl,3-oxa-6-azaspiro[3.3]heptanylpyrimidinyl,6-thia-2-azaspiro[3.3]-heptanylpyrimidinyl,2-oxa-6-azaspiro[3.4]octanylpyrimidinyl,2-oxa-6-azaspiro[3.5]-nonanylpyrimidinyl,2-oxa-7-azaspiro[3.5]nonanylpyrimidinyl or2,4,8-triazaspiro[4.5]-decanylpyrimidinyl, any of which groups may beoptionally substituted by one or more substituents.

Appropriately, R¹¹ represents phenyl or pyrimidinyl, either of whichgroups may be optionally substituted by one or more substituents.

Typical examples of optional substituents on R¹¹ include one, two orthree substituents independently selected from halogen, halo(C₁₋₆)alkyl,cyano, cyano(C₁₋₆)alkyl, nitro(C₁₋₆)alkyl, C₁₋₆ alkyl, trifluoromethyl,difluoroethyl, trifluoroethyl, C₂₋₆ alkenyl, hydroxy,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, trifluoroethoxy,carboxy(C₃₋₇)cycloalkyloxy, pentafluorothio, C₁₋₆ alkylthio, C₁₋₆alkylsulphonyl, (C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, oxo, amino,amino(C₁₋₆)alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,(C₁₋₆)alkoxy(C₁₋₆)alkylamino,N—[(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino,(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, C₁₋₆ alkylsulphonylamino,N—[(C₁₋₆)alkyl]-N—[(C₁₋₆)alkylsulphonyl]amino,bis[(C₁₋₆)alkylsulphonyl]amino,N—[(C₁₋₆)alkyl]-N-[carboxy(C₁₋₆)alkyl]amino,carboxy(C₃₋₇)cycloalkylamino, carboxy(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,formyl, C₂₋₆ alkylcarbonyl, (C₂₋₆)alkyl-carbonyloxy(C₁₋₆)alkyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonylmethylidenyl, acarboxylic acid isostere or prodrug moiety Ω as defined herein,—(C₁₋₆)alkyl-Ω, aminocarbonyl, aminosulphonyl, (C₁₋₆)alkylsulphoximinyland [(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]sulphoximinyl.

Suitable examples of optional substituents on R¹¹ include one, two orthree substituents independently selected from hydroxy(C₁₋₆)alkyl andC₁₋₆ alkylsulphonyl.

Typical examples of particular substituents on R¹¹ include one, two orthree substituents independently selected from fluoro, chloro,fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitromethyl, methyl,ethyl, isopropyl, trifluoromethyl, difluoroethyl, ethenyl, hydroxy,hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy, trifluoroethoxy,carboxycyclobutyloxy, pentafluorothio, methylthio, methylsulphonyl,methylsulphonylethyl, oxo, amino, aminomethyl, aminoisopropyl,methylamino, dimethylamino, methoxyethylamino,N-(hydroxyethyl)-N-(methyl)amino, acetylaminomethyl,methylsulphonylamino, N-methyl-N-(methylsulphonyl)amino,bis(methylsulphonyl)amino, N-(carboxy ethyl)-N-(methyl)amino,carboxycyclopentylamino, carboxycyclopropylmethylamino, formyl, acetyl,acetoxyisopropyl, carboxy, carboxymethyl, carboxyethyl,methoxy-carbonyl, ethoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl,methoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl,morpholinylethoxycarbonyl, ethoxycarbonylmethylidenyl,methylsulphonylaminocarbonyl, acetylaminosulphonyl,methoxyaminocarbonyl, tetrazolyl, tetrazolylmethyl, hydroxyoxadiazolyl,aminocarbonyl, aminosulphonyl, methylsulphoximinyl and(methyl)(N-methyl)sulphoximinyl.

Suitable examples of particular substituents on R¹¹ include one, two orthree substituents independently selected from hydroxyisopropyl andmethylsulphonyl.

In a particular embodiment, R¹¹ is substituted by hydroxy(C₁₋₆)alkyl. Inone aspect of that embodiment, R¹¹ is substituted by hydroxyisopropyl,especially 2-hydroxyprop-2-yl.

Selected values of R¹¹ include bromo, iodo, methoxycarbonylethyl,ethoxycarbonylethyl, hydroxybutynyl, chlorophenyl, hydroxyphenyl,pentafluoro-thiophenyl, methylsulphonylphenyl, aminomethylphenyl,aminoisopropylphenyl, acetyl-aminomethylphenyl, acetylphenyl,methoxycarbonylphenyl, aminocarbonylphenyl, aminosulphonylphenyl,acetylaminosulphonylphenyl, (methoxycarbonyl)(methyl)-pyrrolidinyl,oxopiperidinyl, ethoxycarbonylpiperidinyl, methylsulphonylpiperazinyl,morpholinyl, methylsulphonyl-1,2,3,6-tetrahydropyridinyl,acetyl-1,2,3,6-tetrahydropyridinyl,tert-butoxycarbonyl-1,2,3,6-tetrahydropyridinyl,methoxycarbonylmethyl-1,2,3,6-tetrahydropyridinyl, benzofuryl, thienyl,indolyl, pyrazolyl, methylpyrazolyl, dimethylpyrazolyl,(methyl)[N-methyl-N-(methylsulfonyl)amino]pyrazolyl, methylindazolyl,dimethylisoxazolyl, hydroxyisopropylthiazolyl, methylimidazolyl,dimethylimidazolyl, pyridinyl, fluoropyridinyl, cyanopyridinyl,methylpyridinyl, (cyano)-(methyl)pyridinyl, dimethylpyridinyl,trifluoromethylpyridinyl, ethenylpyridinyl, hydroxyisopropylpyridinyl,methoxypyridinyl, (methoxy)(methyl)pyridinyl, isopropoxy-pyridinyl,trifluoroethoxypyridinyl, (methyl)(trifluoroethoxy)pyridinyl,methylsulphonyl-pyridinyl, oxopyridinyl, (methyl)(oxo)pyridinyl,(dimethyl)(oxo)pyridinyl, aminopyridinyl, methylaminopyridinyl,dimethylaminopyridinyl, methoxyethylaminopyridinyl,N-(hydroxyethyl)-N-(methyl)aminopyridinyl,methylsulphonylaminopyridinyl, [bis(methylsulphonyl)amino]pyridinyl,carboxypyridinyl, quinolinyl, hydroxypyridazinyl, pyrimidinyl,fluoroisopropylpyrimidinyl, difluoroethylpyrimidinyl,hydroxyisopropylpyrimidinyl, methoxypyrimidinyl,carboxycyclobutyloxypyrimidinyl, methylthio-pyrimidinyl,methylsulphonylpyrimidinyl, oxopyrimidinyl, aminopyrimidinyl,dimethyl-aminopyrimidinyl, methoxyethylaminopyrimidinyl,N-(carboxyethyl)-N-(methyl)aminopyrimidinyl,carboxycyclopentylaminopyrimidinyl,carboxycyclopropylmethylamino-pyrimidinyl, acetoxyisopropylpyrimidinyl,ethoxycarbonylethylpyrimidinyl, hydroxypyrazinyl,hydroxyisopropylpyrazinyl, pyrrolidinylmethylphenyl,piperazinylmethylphenyl, pyridinylpiperazinyl,carboxycyclohexylpyrazolyl, carboxycyclohexyl-pyridinyl,fluoromethylcyclopropylpyrimidinyl, hydroxycyclopropylpyrimidinyl,acetyl-aminomethylcyclopropylpyrimidinyl, hydroxycyclobutylpyrimidinyl,(difluoro)-(hydroxy)cyclobutylpyrimidinyl,carboxycyclopentylpyrimidinyl, carboxycyclohexyl-pyrimidinyl,(carboxy)(methyl)cyclohexylpyrimidinyl,(carboxy)(hydroxy)cyclohexylpyrimidinyl,carboxymethylcyclohexylpyrimidinyl,ethoxycarbonylcyclohexyl-pyrimidinyl,(methoxycarbonyl)(methyl)cyclohexylpyrimidinyl,(ethoxycarbonyl)-(methyl)cyclohexylpyrimidinyl,carboxycyclohexylpyrazinyl, carboxycyclohexylmethyl-pyrimidinyl,carboxycyclohexenylpyridinyl, carboxycyclohexenylpyrimidinyl,ethoxycarbonylcyclohexenylpyrimidinyl,carboxybicyclo[3.1.0]hexanylpyridinyl,carboxybicyclo[3.1.0]hexanylpyrimidinyl,ethoxycarbonylbicyclo[3.1.0]hexanylpyrimidinyl,carboxybicyclo[4.1.0]heptanylpyrimidinyl,carboxybicyclo[2.2.2]octanylpyrimidinyl, pyrrolidinylpyridinyl,hydroxypyrrolidinylpyridinyl, hydroxytetrahydropyranylpyridinyl,piperidinylpyridinyl, acetylpiperidinylpyridinyl,(carboxy)(methyl)piperidinylpyridinyl,[(carboxy)(methyl)piperidinyl](fluoro)pyridinyl,Rcarboxy)(methyl)piperidinylKchloro)pyridinyl, piperazinylpyridinyl,(methyl)-(piperazinyl)pyridinyl, cyanoethylpiperazinylpyridinyl,trifluoroethylpiperazinylpyridinyl, methylsulphonylpiperazinylpyridinyl,methylsulphonylethylpiperazinylpyridinyl, oxopiperazinylpyridinyl,acetylpiperazinylpyridinyl,(tert-butoxycarbonylpiperazinyl)-(methyl)pyridinyl,carboxymethylpiperazinylpyridinyl, carboxyethylpiperazinylpyridinyl,ethoxycarbonylmethylpiperazinylpyridinyl,ethoxycarbonylethylpiperazinylpyridinyl, morpholinylpyridinyl,thiomorpholinylpyridinyl, oxothiomorpholinylpyridinyl,dioxothiomorpholinylpyridinyl, oxodiazepanylpyridinyl,fluorooxetanylpyrimidinyl, hydroxyoxetanylpyrimidinyl,difluoroazetidinylpyrimidinyl, hydroxyazetidinyl-pyrimidinyl,(hydroxy)(methyl)azetidinylpyrimidinyl,(hydroxy)(trifluoromethyl)-azetidinylpyrimidinyl,carboxyazetidinylpyrimidinyl,(tert-butoxycarbonyl)(hydroxy)-azetidinylpyrimidinyl,tetrazolylazetidinylpyrimidinyl, hydroxytetrahydrofuranyl-pyrimidinyl,hydroxypyrrolidinylpyrimidinyl, carboxypyrrolidinylpyrimidinyl,(carboxy)-(methyl)pyrrolidinylpyrimidinyl,carboxymethylpyrrolidinylpyrimidinyl,ethoxycarbonyl-pyrrolidinylpyrimidinyl,fluorotetrahydropyranylpyrimidinyl,hydroxytetrahydropyranyl-pyrimidinyl, difluoropiperidinylpyrimidinyl,(cyano)(methyl)piperidinylpyrimidinyl,(hydroxy)(nitromethyl)piperidinylpyrimidinyl,(hydroxy)(methyl)piperidinylpyrimidinyl,(hydroxy)(trifluoromethyl)piperidinylpyrimidinyl,(hydroxymethyl)(methyl)piperidinylpyrimidinyl,methylsulphonylpiperidinylpyrimidinyl, oxopiperidinylpyrimidinyl,(formyl)(methyl)piperidinylpyrimidinyl, carboxypiperidinylpyrimidinyl,(carboxy)-(fluoro)piperidinylpyrimidinyl,(carboxy)(methyl)piperidinylpyrimidinyl,(carboxy)-(ethyl)piperidinylpyrimidinyl,(carboxy)(trifluoromethyl)piperidinylpyrimidinyl,(carboxy)(hydroxy)piperidinylpyrimidinyl,(carboxy)(hydroxymethyl)piperidinylpyrimidinyl,(carboxy)(methoxy)piperidinylpyrimidinyl,(amino)(carboxy)piperidinylpyrimidinyl,carboxymethylpiperidinylpyrimidinyl,methoxycarbonylpiperidinyl-pyrimidinyl,ethoxycarbonylpiperidinylpyrimidinyl,(ethoxycarbonyl)(fluoro)piperidinylpyrimidinyl,(methoxycarbonyl)(methyl)piperidinylpyrimidinyl,(ethyl)(methoxy-carbonyl)piperidinylpyrimidinyl,(isopropyl)(methoxycarbonyl)piperidinylpyrimidinyl,(ethoxycarbonyl)(methyl)piperidinylpyrimidinyl,(n-butoxycarbonyl)(methyl)piperidinylpyrimidinyl,(ethoxycarbonyl)(trifluoromethyl)piperidinylpyrimidinyl,(ethoxycarbonyl)-(hydroxymethyl)piperidinylpyrimidinyl,(methoxy)(methoxycarbonyl)piperidinylpyrimidinyl,(carboxy)(methoxycarbonyl)piperidinylpyrimidinyl,(methyl)-(morpholinylethoxycarbonyl)piperidinylpyrimidinyl,ethoxycarbonylmethylpiperidinyl-pyrimidinyl,methylsulphonylaminocarbonylpiperidinylpyrimidinyl,acetylamino-sulphonylpiperidinylpyrimidinyl,methoxyaminocarbonylpiperidinylpyrimidinyl,tetrazolylpiperidinylpyrimidinyl,hydroxyoxadiazolylpiperidinylpyrimidinyl,amino-sulphonylpiperidinylpyrimidinyl, piperazinylpyrimidinyl,methylsulphonylpiperazinyl-pyrimidinyl, oxopiperazinylpyrimidinyl,carboxypiperazinylpyrimidinyl, carboxyethyl-piperazinylpyrimidinyl,tert-butoxycarbonylpiperazinylpyrimidinyl,tetrazolylmethyl-piperazinylpyrimidinyl,trioxohexahydro-[1,2,5]thiadiazolo[2,3-c]pyrazinylpyrimidinyl,morpholinylpyrimidinyl, dimethylmorpholinylpyrimidinyl,hydroxymethylmorpholinyl-pyrimidinyl, carboxymorpholinylpyrimidinyl,(carboxy)(methyl)morpholinylpyrimidinyl,carboxymethylmorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl,dioxo-thiomorpholinylpyrimidinyl, carboxyazepanylpyrimidinyl,carboxyoxazepanyl-pyrimidinyl, oxodiazepanylpyrimidinyl,(oxodiazepanyl)(trifluoromethyl)pyrimidinyl,(oxodiazepanyl)(methoxy)pyrimidinyl, (methyl)(oxo)diazepanylpyrimidinyl,dioxo-thiadiazepanylpyrimidinyl, hydroxyoxetanylpyrazinyl,(carboxy)(methyl)piperidinylpyrazinyl,(ethoxycarbonyl)(methyl)piperidinylpyrazinyl, morpholinylmethylthienyl,morpholinylethylpyrazolyl, carboxy-3-azabicyclo[3.1.0]hexanylpyridinyl,carboxy-3-azabicyclo[3.1.0]hexanylpyridazinyl,carboxy-3-azabicyclo[3.1.0]hexanylpyrimidinyl,(carboxy)(methyl)-3-azabicyclo[3.1.0]hexanylpyrimidinyl,methoxycarbonyl-3-azabicyclo[3.1.0]hexanylpyrimidinyl,ethoxycarbonyl-3-azabicyclo[3.1.0]hexanylpyrimidinyl,2-oxa-5-azabicyclo[2.2.1]heptanylpyrimidinyl,carboxy-2-oxa-5-azabicyclo-[2.2.1]heptanylpyrimidinyl,carboxy-3-azabicyclo[3.1.1]heptanylpyrimidinyl,6-oxa-3-azabicyclo[3.1.1]heptanylpyrimidinyl,carboxy-3-azabicyclo[4.1.0]heptanylpyridinyl,carboxy-3-azabicyclo[4.1.0]heptanylpyrimidinyl,methoxycarbonyl-3-azabicyclo[4.1.0]-heptanylpyrimidinyl,ethoxycarbonyl-3-azabicyclo[4.1.0]heptanylpyrimidinyl,(hydroxy)-(methyl)(oxo)-2-oxabicyclo[2.2.2]octanylpyrimidinyl,carboxy-3-azabicyclo[3.2.1]-octanylpyrimidinyl,methoxycarbonyl-3-azabicyclo[3.2.1]octanylpyrimidinyl,oxo-8-azabicyclo[3.2.1]octanylpyrimidinyl,ethoxycarbonylmethylidenyl-8-azabicyclo[3.2.1]-octanylpyrimidinyl,3-oxa-8-azabicyclo[3.2.1]octanylpyrimidinyl,oxo-3,6-diazabicyclo-[3.2.2]nonanylpyrimidinyl,carboxy-3-oxa-7-azabicyclo[3.3.1]nonanylpyrimidinyl,3,7-dioxa-9-azabicyclo[3.3.1]nonanylpyrimidinyl,carboxy-5-azaspiro[2.3]hexanylpyrimidinyl,(carboxy)(methyl)-5-azaspiro[2.3]hexanylpyrimidinyl,carboxy-5-azaspiro-[2.4]heptanylpyrimidinyl,carboxy-2-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro-[3.3]heptanylpyrimidinyl,3-oxa-6-azaspiro[3.3]heptanylpyrimidinyl,dioxo-6-thia-2-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro[3.4]octanylpyrimidinyl,2-oxa-6-azaspiro[3.5]nonanylpyrimidinyl,2-oxa-7-azaspiro[3.5]nonanylpyrimidinyl and(dioxo)(methyl)-2,4,8-triazaspiro[4.5]decanylpyrimidinyl.

Illustrative values of R¹¹ include methylsulphonylphenyl andhydroxyisopropylpyrimidinyl.

Typically, R¹⁵ and R¹⁶ may independently represent hydrogen, fluoro,chloro, bromo, cyano, nitro, methyl, isopropyl, trifluoromethyl,hydroxy, methoxy, difluoro-methoxy, trifluoromethoxy, methylthio,methylsulfinyl, methylsulfonyl, amino, methylamino, tert-butylamino,dimethylamino, phenylamino, acetylamino, methylsulfonylamino, formyl,acetyl, cyclopropylcarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl,piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, carboxy,methoxycarbonyl, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl anddimethylaminosulfonyl.

Suitably, R¹⁵ and R¹⁶ may independently represent hydrogen, chloro,methyl, methoxy or difluoromethoxy.

Typical values of R¹⁵ include hydrogen, halogen, C₁₋₆ alkyl,trifluoromethyl, C₁₋₆ alkoxy, difluoromethoxy and trifluoromethoxy.

Suitable values of R¹⁵ include hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆alkoxy and difluoromethoxy.

In a first embodiment, R¹⁵ represents hydrogen. In a second embodiment,R¹⁵ represents halogen. In a first aspect of that embodiment, R¹⁵represents fluoro. In a second aspect of that embodiment, R¹⁵ representschloro. In a third embodiment, R¹⁵ represents C₁₋₆ alkyl. In one aspectof that embodiment, R¹⁵ represents methyl. In a fourth embodiment, R¹⁵represents trifluoromethyl. In a fifth embodiment, R¹⁵ represents C₁₋₆alkoxy. In one aspect of that embodiment, R¹⁵ represents methoxy. In asixth embodiment, R¹⁵ represents difluoromethoxy. In a seventhembodiment, R¹⁵ represents trifluoromethoxy.

Selected values of R¹⁵ include hydrogen, fluoro, chloro, methyl,trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy.

Illustrative values of R¹⁵ include hydrogen, chloro, methyl, methoxy anddifluoro-methoxy.

Typical values of R¹⁶ include hydrogen, halogen, cyano, C₁₋₆ alkyl,trifluoro-methyl, difluoromethoxy and amino.

In a first embodiment, R¹⁶ represents hydrogen. In a second embodiment,R¹⁶ represents halogen. In a first aspect of that embodiment, R¹⁶represents fluoro. In a second aspect of that embodiment, R¹⁶ representschloro. In a third embodiment, R¹⁶ represents cyano. In a fourthembodiment, R¹⁶ represents C₁₋₆ alkyl. In one aspect of that embodiment,R¹⁶ represents methyl. In a fifth embodiment, R¹⁶ representstrifluoro-methyl. In a sixth embodiment, R¹⁶ represents difluoromethoxy.In a seventh embodiment, R¹⁶ represents amino.

Selected values of R¹⁶ include hydrogen, fluoro, chloro, cyano, methyl,trifluoro-methyl, difluoromethoxy and amino.

In a particular embodiment, R¹⁶ is attached at the para-position of thephenyl ring relative to the integer R¹⁵.

A particular sub-group of the compounds of formula (IIA) above isrepresented by the compounds of formula (IIB) and N-oxides thereof, andpharmaceutically acceptable salts and solvates thereof, and glucuronidederivatives thereof, and co-crystals thereof:

wherein

V represents C—R²² or N;

R²¹ represents hydrogen, halogen, halo(C₁₋₆)alkyl, cyano, C₁₋₆ alkyl,trifluoro-methyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, hydroxy,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, (C₁₋₆)alkoxy-(C₁₋₆)alkyl,difluoromethoxy, trifluoromethoxy, trifluoroethoxy,carboxy(C₃₋₇)cycloalkyloxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulphonyl,(C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, amino, amino-(C₁₋₆)alkyl, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, (C₁₋₆)alkoxy(C₁₋₆)alkylamino,N—[(C₁₋₆)-alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino, C₂₋₆ alkylcarbonylamino,(C₂₋₆)alkylcarbonylamino-(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonylamino,N—[(C₁₋₆)alkyl]-N-[carboxy(C₁-C₆)alkyl]amino,carboxy(C₃₋₇)cycloalkylamino, carboxy(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,C₁₋₆ alkylsulphonylamino, C₁₋₆ alkylsulphonylamino(C₁₋₆)alkyl, formyl,C₂₋₆ alkylcarbonyl, (C₂₋₆)alkylcarbonyloxy(C₁₋₆)alkyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl, C₂₋₆alkoxycarbonylmethylidenyl, aminocarbonyl, C₁₋₆ alkylaminocarbonyl,di(C₁₋₆)alkylaminocarbonyl, aminosulphonyl, C₁₋₆ alkylaminosulphonyl,di(C₁₋₆)alkylaminosulphonyl, (C₁₋₆)alkylsulphoximinyl or[(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]sulphoximinyl; or R²¹ represents(C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl(C₁₋₆)alkyl, (C₄₋₇)cycloalkenyl,(C₄₋₉)bicycloalkyl, (C₃₋₇)heterocycloalkyl, (C₃₋₇)heterocycloalkenyl,(C₄₋₉)heterobicycloalkyl or (C₄₋₉)spiroheterocycloalkyl, any of whichgroups may be optionally substituted by one or more substituents;

R²² represents hydrogen, halogen or C₁₋₆ alkyl;

R²³ represents hydrogen, C₁₋₆ alkyl, trifluoromethyl or C₁₋₆ alkoxy; and

q, A, G, E, Q, Z, R¹⁵ and R¹⁶ are as defined above.

In one embodiment, V represents C—R²². In another embodiment, Vrepresents N.

Typically, R²¹ represents hydrogen, halogen, halo(C₁₋₆)alkyl, cyano,C₁₋₆ alkyl, trifluoromethyl, C₂₋₆ alkenyl, hydroxy, hydroxy(C₁₋₆)alkyl,C₁₋₆ alkoxy, trifluoroethoxy, carboxy(C₃₋₇)cycloalkyloxy, C₁₋₆alkylthio, C₁₋₆ alkylsulphonyl, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, (C₁₋₆)alkoxy(C₁₋₆)alkylamino,N—[(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]-amino,N—[(C₁₋₆)alkyl]-N-[carboxy(C₁₋₆)alkyl]amino,carboxy(C₃₋₇)cycloalkylamino, carboxy(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,C₁₋₆ alkylsulphonylamino, (C₂₋₆)alkylcarbonyl-oxy(C₁₋₆)alkyl, carboxy,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl or C₂₋₆alkoxycarbonylmethylidenyl; or R²¹ represents (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl-(C₁₋₆)alkyl, (C₄₋₇)cycloalkenyl, (C₄₋₉)bicycloalkyl,(C₃₋₇)heterocycloalkyl, (C₄₋₉)heterobicycloalkyl or(C₄₋₉)spiroheterocycloalkyl, any of which groups may be optionallysubstituted by one or more substituents.

Where R²¹ represents an optionally substituted (C₃₋₇)cycloalkyl group,typical values include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland cycloheptyl, any of which groups may be optionally substituted byone or more substituents.

Where R²¹ represents an optionally substituted(C₃₋₇)cycloalkyl(C₁₋₆)alkyl group, a typical value is cyclohexylmethyl,which group may be optionally substituted by one or more substituents.

Where R²¹ represents an optionally substituted (C₄₋₇)cycloalkenyl group,typical values include cyclobutenyl, cyclopentenyl, cyclohexenyl andcycloheptenyl, any of which groups may be optionally substituted by oneor more substituents.

Where R²¹ represents an optionally substituted (C₄₋₉)bicycloalkyl group,typical values include bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl andbicyclo[2.2.2]octanyl, any of which groups may be optionally substitutedby one or more substituents.

Where R²¹ represents an optionally substituted (C₃₋₇)heterocycloalkylgroup, typical values include oxetanyl, azetidinyl, tetrahydrofuranyl,pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,hexahydro-[1,2,5]thiadiazolo[2,3-c]pyrazinyl, morpholinyl,thiomorpholinyl, azepanyl, oxazepanyl, diazepanyl and thiadiazepanyl,any of which groups may be optionally substituted by one or moresubstituents.

Where R²¹ represents an optionally substituted (C₃₋₇)heterocycloalkenylgroup, a typical value is optionally substituted1,2,3,6-tetrahydropyridinyl.

Where R²¹ represents an optionally substituted (C₄₋₉)heterobicycloalkylgroup, typical values include 3-azabicyclo[3.1.0]hexanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl,6-oxa-3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]-heptanyl,2-oxabicyclo[2.2.2]octanyl, quinuclidinyl,2-oxa-5-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl,8-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl,3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.2]nonanyl,3-oxa-7-azabicyclo-[3.3.1]nonanyl, 3,7-dioxa-9-azabicyclo[3.3.1]nonanyland 3,9-diazabicyclo[4.2.1]nonanyl, any of which groups may beoptionally substituted by one or more substituents.

Where R²¹ represents an optionally substituted(C₄₋₉)spiroheterocycloalkyl group, typical values include5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]heptanyl,2-azaspiro[3.3]-heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl,3-oxa-6-azaspiro[3.3]heptanyl, 6-thia-2-azaspiro[3.3]heptanyl,2-oxa-6-azaspiro[3.4]octanyl, 2-oxa-6-azaspiro[3.5]nonanyl,2-oxa-7-azaspiro[3.5]nonanyl and 2,4,8-triazaspiro[4.5]decanyl, any ofwhich groups may be optionally substituted by one or more substituents.

Illustratively, R²¹ represents hydroxy, hydroxy(C₁₋₆)alkyl, methoxy,carboxycyclobutyloxy, methylthio, methylsulphonyl, methylamino,N-[carboxyethyl]-N-methylamino, carboxycyclopentylamino,carboxycyclopropylmethylamino or ethoxycarbonylethyl; or R²¹ representscyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl,cyclohexenyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl,bicyclo[2.2.2]-octanyl, oxetanyl, azetidinyl, tetrahydrofuranyl,pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazinyl, morpholinyl,thiomorpholinyl, azepanyl, oxazepanyl, diazepanyl, thiadiazepanyl,3-azabicyclo[3.1.0]-hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl,3-azabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl,3-azabicyclo[4.1.0]heptanyl, 2-oxabicyclo[2.2.2]octanyl,3-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl,3-oxa-8-azabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.2]nonanyl,3-oxa-7-azabicyclo[3.3.1]nonanyl, 3,7-dioxa-9-azabicyclo[3.3.1]nonanyl,5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]heptanyl,2-azaspiro-[3.3]heptanyl, 3-oxa-6-azaspiro[3.3]heptanyl or6-thia-2-azaspiro[3.3]heptanyl, any of which groups may be optionallysubstituted by one or more substituents.

Examples of optional substituents which may be present on R²¹ includeone, two or three substituents independently selected from halogen,halo(C₁₋₆)alkyl, cyano, cyano-(C₁₋₆)alkyl, nitro, nitro(C₁₋₆)alkyl, C₁₋₆alkyl, trifluoromethyl, trifluoroethyl, C₂₋₆ alkenyl, hydroxy,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, difluoromethoxy, trifluoromethoxy,trifluoroethoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulphonyl,(C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, oxo, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, C₂₋₆ alkylcarbonylamino,(C₂₋₆)alkylcarbonylamino-(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonylamino, C₁₋₆alkylsulphonylamino, formyl, C₂₋₆ alkylcarbonyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl,morpholinyl-(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl, C₂₋₆alkoxycarbonylmethylidenyl, a carboxylic acid isostere or prodrug moietyΩ as defined herein, —(C₁₋₆)alkyl-Ω, aminocarbonyl, C₁₋₆alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl, aminosulphonyl,di(C₁₋₆)alkylaminosulphonyl, (C₁₋₆)alkylsulphoximinyl and[(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]-sulphoximinyl.

Suitable examples of particular substituents on R²¹ include one, two orthree substituents independently selected from fluoro, fluoromethyl,chloro, bromo, cyano, cyanomethyl, cyanoethyl, nitro, nitromethyl,methyl, ethyl, isopropyl, trifluoromethyl, trifluoroethyl, ethenyl,hydroxy, hydroxymethyl, methoxy, ethoxy, difluoromethoxy,trifluoromethoxy, trifluoroethoxy, methylthio, methylsulphonyl,methylsulphonylmethyl, methylsulphonylethyl, oxo, amino, methylamino,dimethylamino, acetylamino, acetylaminomethyl, methoxycarbonylamino,ethoxycarbonylamino, tert-butoxycarbonylamino, methylsulphonylamino,formyl, acetyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl,ethoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl,morpholinylethoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl,ethoxycarbonylethyl, ethoxycarbonylmethylidenyl, acetylaminosulphonyl,methoxyaminocarbonyl, tetrazolyl, tetrazolylmethyl, hydroxyoxadiazolyl,aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl,methylsulphonylaminocarbonyl, aminosulphonyl, methylaminosulphonyl,dimethylaminosulphonyl, methylsulphoximinyl and(methyl)(N-methyl)sulphoximinyl.

Typically, R²¹ represents hydrogen, fluoro, fluoroisopropyl, cyano,methyl, trifluoromethyl, ethenyl, hydroxy, hydroxyisopropyl, methoxy,isopropoxy, trifluoroethoxy, carboxycyclobutyloxy, methylthio,methylsulphonyl, amino, methylamino, dimethylamino, methoxyethylamino,N-(hydroxyethyl)-N-(methyl)amino, N-[carboxyethyl]-N-methylamino,carboxycyclopentylamino, carboxycyclopropylmethylamino,methylsulphonylamino, acetoxyisopropyl, carboxy, ethoxycarbonylethyl,fluoromethyl-cyclopropyl, hydroxycyclopropyl,(difluoro)(hydroxy)cyclopropyl, acetylaminomethyl-cyclopropyl,hydroxycyclobutyl, carboxycyclopentyl, carboxycyclohexyl,(carboxy)-(methyl)cyclohexyl, (carboxy)(hydroxy)cyclohexyl,carboxymethylcyclohexyl, ethoxycarbonylcyclohexyl,(methoxycarbonyl)(methyl)cyclohexyl,(ethoxycarbonyl)-(methyl)cyclohexyl, carboxycyclohexylmethyl,carboxycyclohexenyl, ethoxycarbonyl-cyclohexenyl,carboxybicyclo[3.1.0]hexanyl, ethoxycarbonylbicyclo[3.1.0]hexanyl,carboxybicyclo[4.1.0]heptanyl, carboxybicyclo[2.2.2]octanyl,fluorooxetanyl, hydroxyoxetanyl, difluoroazetidinyl, hydroxyazetidinyl,(hydroxy)(methyl)azetidinyl, (hydroxy)(trifluoromethyl)azetidinyl,carboxyazetidinyl, (tert-butoxycarbonyl)(hydroxy)-azetidinyl,tetrazolylazetidinyl, hydroxytetrahydrofuranyl, pyrrolidinyl,hydroxy-pyrrolidinyl, carboxypyrrolidinyl,(carboxy)(methyl)pyrrolidinyl, carboxymethyl-pyrrolidinyl,ethoxycarbonylpyrrolidinyl, fluorotetrahydropyranyl,hydroxytetrahydropyranyl, piperidinyl, difluoropiperidinyl,(cyano)(methyl)piperidinyl, (hydroxy)-(nitromethyl)piperidinyl,(hydroxy)(methyl)piperidinyl, (hydroxy)(trifluoromethyl)-piperidinyl,(hydroxymethyl)(methyl)piperidinyl, methylsulphonylpiperidinyl,oxopiperidinyl, (formyl)(methyl)piperidinyl, acetylpiperidinyl,carboxypiperidinyl, (carboxy)(fluoro)piperidinyl,(carboxy)(methyl)piperidinyl, (carboxy)(ethyl)piperidinyl,(carboxy)(trifluoromethyl)piperidinyl, (carboxy)(hydroxy)piperidinyl,(carboxy)-(hydroxymethyl)piperidinyl, (carboxy)(methoxy)piperidinyl,(amino)(carboxy)piperidinyl, carboxymethylpiperidinyl,methoxycarbonylpiperidinyl, (methoxycarbonyl)(methyl)-piperidinyl,(ethyl)(methoxycarbonyl)piperidinyl,(isopropyl)(methoxycarbonyl)-piperidinyl,(methoxy)(methoxycarbonyl)piperidinyl,(carboxy)(methoxycarbonyl)-piperidinyl, ethoxycarbonylpiperidinyl,(ethoxycarbonyl)(fluoro)piperidinyl,(ethoxycarbonyl)(methyl)piperidinyl,(ethoxycarbonyl)(trifluoromethyl)piperidinyl,(ethoxycarbonyl)(hydroxymethyl)piperidinyl,(n-butoxycarbonyl)(methyl)piperidinyl,(methyl)(morpholinylethoxycarbonyl)piperidinyl,ethoxycarbonylmethylpiperidinyl,methylsulphonylaminocarbonylpiperidinyl,acetylaminosulphonylpiperidinyl, methoxyaminocarbonylpiperidinyl,tetrazolylpiperidinyl, hydroxyoxadiazolylpiperidinyl,aminosulphonylpiperidinyl, piperazinyl, cyanoethylpiperazinyl,trifluoroethylpiperazinyl, methylsulphonylpiperazinyl,methylsulphonylethylpiperazinyl, oxopiperazinyl, acetyl-piperazinyl,carboxypiperazinyl, tert-butoxycarbonylpiperazinyl,carboxymethyl-piperazinyl, carboxyethylpiperazinyl,ethoxycarbonylmethylpiperazinyl, ethoxycarbonyl-ethylpiperazinyl,tetrazolylmethylpiperazinyl,trioxohexahydro-[1,2,5]thiadiazolo[2,3-a]-pyrazinyl, morpholinyl,dimethylmorpholinyl, hydroxymethylmorpholinyl, carboxy-morpholinyl,(carboxy)(methyl)morpholinyl, carboxymethylmorpholinyl, thiomorpholinyl,oxothiomorpholinyl, dioxothiomorpholinyl, carboxyazepanyl,carboxyoxazepanyl, oxodiazepanyl, (methyl)(oxo)diazepanyl,dioxothiadiazepanyl, carboxy-3-azabicyclo-[3.1.0]hexanyl,(carboxy)(methyl)-3-azabicyclo[3.1.0]hexanyl,methoxycarbonyl-3-azabicyclo[3.1.0]hexanyl,ethoxycarbonyl-3-azabicyclo[3.1.0]hexanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl,carboxy-2-oxa-5-azabicyclo[2.2.1]heptanyl,carboxy-3-azabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl,carboxy-3-azabicyclo-[4.1.0]heptanyl,methoxycarbonyl-3-azabicyclo[4.1.0]heptanyl,ethoxycarbonyl-3-azabicyclo[4.1.0]heptanyl,(hydroxy)(methyl)(oxo)-2-oxabicyclo[2.2.2]octanyl,carboxy-3-azabicyclo[3.2.1]octanyl,methoxycarbonyl-3-azabicyclo[3.2.1]octanyl,oxo-8-azabicyclo[3.2.1]octanyl,ethoxycarbonylmethylidenyl-8-azabicyclo[3.2.1]octanyl,3-oxa-8-azabicyclo[3.2.1]octanyl, oxo-3,6-diazabicyclo[3.2.2]nonanyl,carboxy-3-oxa-7-azabicyclo[3.3.1]nonanyl,3,7-dioxa-9-azabicyclo[3.3.1]nonanyl, carboxy-5-azaspiro-[2.3]hexanyl,(carboxy)(methyl)-5-azaspiro[2.3]hexanyl,carboxy-5-azaspiro[2.4]heptanyl, carboxy-2-azaspiro[3.3]heptanyl,2-oxa-6-azaspiro[3.3]heptanyl, 3-oxa-6-azaspiro[3.3]-heptanyl,dioxo-6-thia-2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.4]octanyl,2-oxa-6-azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro[3.5]nonanyl or(dioxo)(methyl)-2,4,8-triazaspiro-[4.5]decanyl.

In a particular embodiment, R²¹ represents hydroxy(C₁₋₆)alkyl. In oneaspect of that embodiment, R²¹ represents hydroxyisopropyl, especially2-hydroxyprop-2-yl.

Generally, R²² represents hydrogen or C₁₋₆ alkyl.

Suitably, R²² represents hydrogen, chloro or methyl.

Typically, R²² represents hydrogen or methyl.

In one embodiment, R²² represents hydrogen. In another embodiment, R²²represents C₁₋₆ alkyl, especially methyl. In a further embodiment, R²²represents halogen. In one aspect of that embodiment, R²² representsfluoro. In another aspect of that embodiment, R²² represents chloro.

Generally, R²³ represents hydrogen or C₁₋₆ alkyl.

Suitably, R²³ represents hydrogen, methyl, trifluoromethyl or methoxy.

Typically, R²³ represents hydrogen or methyl.

In one embodiment, R²³ represents hydrogen. In another embodiment, R²³represents C₁₋₆ alkyl, especially methyl. In a further embodiment, R²³represents trifluoromethyl. In an additional embodiment, R²³ representsC₁₋₆ alkoxy, especially methoxy.

Particular sub-groups of the compounds of formula (IIB) above arerepresented by the compounds of formula (IIC), (IID), (IIE), (IIF),(IIG), (IIH), (IIJ), (IIK) and (IIL), and N-oxides thereof, andpharmaceutically acceptable salts and solvates thereof, and glucuronidederivatives thereof, and co-crystals thereof:

wherein

T represents —CH₂— or —CH₂CH₂—;

U represents C(O) or S(O)₂;

W represents O, S, S(O), S(O)₂, S(O)(NR⁶), N(R³¹) or C(R³²)(R³³);

-M- represents —CH₂— or —CH₂CH₂—;

R³¹ represents hydrogen, cyano(C₁₋₆)alkyl, C₁₋₆ alkyl, trifluoromethyl,trifluoroethyl, C₁₋₆ alkylsulphonyl, (C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl,formyl, C₂₋₆ alkylcarbonyl, carboxy, carboxy(C₁₋₆)alkyl, C₂₋₆alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl, a carboxylic acidisostere or prodrug moiety Ω, —(C₁₋₆)alkyl-Ω, aminocarbonyl, C₁₋₆alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl, aminosulphonyl ordi(C₁₋₆)alkylaminosulphonyl;

R³² represents hydrogen, halogen, cyano, hydroxy, hydroxy(C₁₋₆)alkyl,C₁₋₆ alkylsulphonyl, formyl, C₂₋₆ alkylcarbonyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,aminosulphonyl, (C₁₋₆)alkylsulphoximinyl,[(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]sulphoximinyl, a carboxylic acid isostere orprodrug moiety Ω, or —(C₁₋₆)alkyl-Ω;

R³³ represents hydrogen, halogen, C₁₋₆ alkyl, trifluoromethyl, hydroxy,hydroxy-(C₁₋₆)alkyl, C₁₋₆ alkoxy, amino or carboxy;

R³⁴ represents hydrogen, halogen, halo(C₁₋₆)alkyl, hydroxy, C₁₋₆ alkoxy,C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl, C₁₋₆ alkylsulphonyl, amino, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, (C₂₋₆)alkylcarbonylamino,(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, (C₁₋₆)alkylsulphonylamino or(C₁₋₆)alkylsulphonylamino(C₁₋₆)alkyl; and

q, A, G, E, Q, Z, R⁶, V, R¹⁵, R¹⁶, R²³ and Ω are as defined above.

In a first embodiment, T represents —CH₂—. In a second embodiment, Trepresents —CH₂CH₂—.

In a first embodiment, U represents C(O). In a second embodiment, Urepresents S(O)₂.

Generally, W represents O, S(O)₂, N(R³¹) or C(R³²)(R³³).

Typically, W represents O, N(R³¹) or C(R³²)(R³³).

In a first embodiment, W represents O. In a second embodiment, Wrepresents S. In a third embodiment, W represents S(O). In a fourthembodiment, W represents S(O)₂. In a fifth embodiment, W representsS(O)(NR⁶). In a sixth embodiment, W represents N(R³¹). In a seventhembodiment, W represents C(R³²)(R³³).

In one embodiment, -M- represents —CH₂—. In another embodiment, -M-represents —CH₂CH₂—.

Typically, R³¹ represents hydrogen, cyano(C₁₋₆)alkyl, C₁₋₆ alkyl,trifluoromethyl, trifluoroethyl, C₁₋₆ alkylsulphonyl,(C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, formyl, C₂₋₆ alkylcarbonyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆alkoxycarbonyl-(C₁₋₆)alkyl, tetrazolyl(C₁₋₆)alkyl, aminocarbonyl, C₁₋₆alkylaminocarbonyl, aminocarbonyl, aminosulphonyl, C₁₋₆alkylaminosulphonyl or di(C₁₋₆)alkylaminosulphonyl.

Typical values of R³¹ include hydrogen, cyanoethyl, methyl, ethyl,isopropyl, trifluoromethyl, trifluoroethyl, methylsulphonyl,methylsulphonylethyl, formyl, acetyl, carboxy, carboxymethyl,carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,ethoxycarbonylmethyl, ethoxycarbonylethyl, tetrazolylmethyl,aminocarbonyl, methylamino-carbonyl, dimethylaminocarbonyl,aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl.

A particular value of R³¹ is hydrogen.

Generally, R³² represents hydrogen, halogen, hydroxy, carboxy,carboxy(C₁₋₆)-alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆alkoxycarbonyl(C₁₋₆)alkyl, a carboxylic acid isostere or prodrug moietyΩ, or —(C₁₋₆)alkyl-Ω.

Typically, R³² represents hydrogen, halogen, cyano, hydroxy,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkylsulphonyl, formyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,aminosulphonyl, (C₁₋₆)alkylsulphoximinyl,[(C₁-C₆)alkyl][N—(C₁₋₆)alkyl]sulphoximinyl,(C₁₋₆)alkylsulphonylaminocarbonyl, (C₂₋₆)alkylcarbonylaminosulphonyl,(C₁₋₆)alkoxyaminocarbonyl, tetrazolyl or hydroxyoxadiazolyl.

Typical values of R³² include hydrogen, fluoro, cyano, hydroxy,hydroxymethyl, methylsulphonyl, formyl, carboxy, carboxymethyl,carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl,ethoxycarbonylethyl, aminosulphonyl, methylsulphoximinyl,(methyl)(N-methyl)sulphoximinyl, methylsulphonylaminocarbonyl,acetylaminosulphonyl, methoxyaminocarbonyl, tetrazolyl andhydroxyoxadiazolyl.

In a selected embodiment, R³² represents carboxy.

Generally, R³³ represents hydrogen, halogen, C₁₋₆ alkyl ortrifluoromethyl.

Selected values of R³³ include hydrogen, fluoro, methyl, ethyl,isopropyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxy, amino andcarboxy.

Particular values of R³³ include hydrogen, fluoro, methyl andtrifluoromethyl.

In a first embodiment, R³³ represents hydrogen. In a second embodiment,R³³ represents halogen. In one aspect of that embodiment, R³³ representsfluoro. In a third embodiment, R³³ represents C₁₋₆ alkyl. In a firstaspect of that embodiment, R³³ represents methyl. In a second aspect ofthat embodiment, R³³ represents ethyl. In a third aspect of thatembodiment, R³³ represents isopropyl. In a fourth embodiment, R³³represents trifluoromethyl. In a fifth embodiment, R³³ representshydroxy. In a sixth embodiment, R³³ represents hydroxy(C₁₋₆)alkyl. Inone aspect of that embodiment, R³³ represents hydroxymethyl. In aseventh embodiment, R³³ represents C₁₋₆ alkoxy. In one aspect of thatembodiment, R³³ represents methoxy. In an eighth embodiment, R³³represents amino. In a ninth embodiment, R³³ represents carboxy.

In a first embodiment, R³⁴ represents hydrogen. In a second embodiment,R³⁴ represents halogen. In one aspect of that embodiment, R³⁴ representsfluoro. In a third embodiment, R³⁴ represents halo(C₁₋₆)alkyl. In oneaspect of that embodiment, R³⁴ represents fluoromethyl. In a fourthembodiment, R³⁴ represents hydroxy. In a fifth embodiment, R³⁴represents C₁₋₆ alkoxy, especially methoxy. In a sixth embodiment, R³⁴represents C₁₋₆ alkylthio, especially methylthio. In a seventhembodiment, R³⁴ represents C₁₋₆ alkylsulphinyl, especiallymethylsulphinyl. In an eighth embodiment, R³⁴ represents C₁₋₆alkylsulphonyl, especially methylsulphonyl. In a ninth embodiment, R³⁴represents amino. In a tenth embodiment, R³⁴ represents C₁₋₆ alkylamino,especially methylamino. In an eleventh embodiment, R³⁴ representsdi(C₁₋₆)alkylamino, especially dimethylamino. In a twelfth embodiment,R³⁴ represents (C₂₋₆)alkylcarbonylamino, especially acetylamino. In athirteenth embodiment, R³⁴ represents(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, especially acetylaminomethyl. In afourteenth embodiment, R³⁴ represents (C₁₋₆)alkylsulphonylamino,especially methylsulphonylamino. In a fifteenth embodiment, R³⁴represents (C₁₋₆)alkylsulphonylamino(C₁₋₆)alkyl, especiallymethylsulphonylaminomethyl.

Typically, R³⁴ represents hydrogen, halogen, halo(C₁₋₆)alkyl, hydroxy or(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl.

Suitably, R³⁴ represents hydrogen, halogen or hydroxy.

Selected values of R³⁴ include hydrogen, fluoro, fluoromethyl, hydroxy,methoxy, methylthio, methylsulphinyl, methylsulphonyl, amino,methylamino, dimethylamino and acetylaminomethyl.

Particular values of R³⁴ include hydrogen, fluoro, fluoromethyl, hydroxyand acetylaminomethyl.

Suitably, R³⁴ represents hydrogen, fluoro or hydroxy.

An alternative sub-class of compounds of formula (IIA) above isrepresented by the compounds of formula (IIM) and N-oxides thereof, andpharmaceutically acceptable salts and solvates thereof, and glucuronidederivatives thereof, and co-crystals thereof:

wherein

q, A, G, E, Q, Z, W, R¹⁵, R¹⁶ and R²¹ are as defined above.

With specific reference to formula (IIM), the integer W is suitably O, Sor N—R³¹, especially S or N—R³¹.

Specific novel compounds in accordance with the present inventioninclude each of the compounds whose preparation is described in theaccompanying Examples, and pharmaceutically acceptable salts andsolvates thereof, and co-crystals thereof.

The compounds in accordance with the present invention are beneficial inthe treatment and/or prevention of various human ailments. These includeautoimmune and inflammatory disorders; neurological andneurodegenerative disorders; pain and nociceptive disorders;cardiovascular disorders; metabolic disorders; ocular disorders; andoncological disorders.

Inflammatory and autoimmune disorders include systemic autoimmunedisorders, autoimmune endocrine disorders and organ-specific autoimmunedisorders. Systemic autoimmune disorders include systemic lupuserythematosus (SLE), psoriasis, psoriatic arthropathy, vasculitis,polymyositis, scleroderma, multiple sclerosis, systemic sclerosis,ankylosing spondylitis, rheumatoid arthritis, non-specific inflammatoryarthritis, juvenile inflammatory arthritis, juvenile idiopathicarthritis (including oligoarticular and polyarticular forms thereof),anaemia of chronic disease (ACD), Still's disease (juvenile and/or adultonset), Behçet's disease and Sjögren's syndrome. Autoimmune endocrinedisorders include thyroiditis. Organ-specific autoimmune disordersinclude Addison's disease, haemolytic or pernicious anaemia, acutekidney injury (AKI; including cisplatin-induced AKI), diabeticnephropathy (DN), obstructive uropathy (including cisplatin-inducedobstructive uropathy), glomerulonephritis (including Goodpasture'ssyndrome, immune complex-mediated glomerulonephritis and antineutrophilcytoplasmic antibodies (ANCA)-associated glomerulonephritis), lupusnephritis (LN), minimal change disease, Graves' disease, idiopathicthrombocytopenic purpura, inflammatory bowel disease (including Crohn'sdisease, ulcerative colitis, indeterminate colitis and pouchitis),pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliarycirrhosis, autoimmune pneumonitis, autoimmune carditis, myastheniagravis, spontaneous infertility, osteoporosis, osteopenia, erosive bonedisease, chondritis, cartilage degeneration and/or destruction,fibrosing disorders (including various forms of hepatic and pulmonaryfibrosis), asthma, rhinitis, chronic obstructive pulmonary disease(COPD), respiratory distress syndrome, sepsis, fever, muscular dystrophy(including Duchenne muscular dystrophy) and organ transplant rejection(including kidney allograft rejection).

Neurological and neurodegenerative disorders include Alzheimer'sdisease, Parkinson's disease, Huntington's disease, ischaemia, stroke,amyotrophic lateral sclerosis, spinal cord injury, head trauma, seizuresand epilepsy.

Cardiovascular disorders include thrombosis, cardiac hypertrophy,hypertension, irregular contractility of the heart (e.g. during heartfailure), and sexual disorders (including erectile dysfunction andfemale sexual dysfunction). Modulators of TNFα function may also be ofuse in the treatment and/or prevention of myocardial infarction (see J.J. Wu et al., JAMA, 2013, 309, 2043-2044).

Metabolic disorders include diabetes (including insulin-dependentdiabetes mellitus and juvenile diabetes), dyslipidemia and metabolicsyndrome.

Ocular disorders include retinopathy (including diabetic retinopathy,proliferative retinopathy, non-proliferative retinopathy and retinopathyof prematurity), macular oedema (including diabetic macular oedema),age-related macular degeneration (ARMD), vascularisation (includingcorneal vascularisation and neovascularisation), retinal vein occlusion,and various forms of uveitis and keratitis.

Oncological disorders, which may be acute or chronic, includeproliferative disorders, especially cancer, and cancer-associatedcomplications (including skeletal complications, cachexia and anaemia).Particular categories of cancer include haematological malignancy(including leukaemia and lymphoma) and non-haematological malignancy(including solid tumour cancer, sarcoma, meningioma, glioblastomamultiforme, neuroblastoma, melanoma, gastric carcinoma and renal cellcarcinoma). Chronic leukaemia may be myeloid or lymphoid. Varieties ofleukaemia include lymphoblastic T cell leukaemia, chronic myelogenousleukaemia (CML), chronic lymphocytic/lymphoid leukaemia (CLL),hairy-cell leukaemia, acute lymphoblastic leukaemia (ALL), acutemyelogenous leukaemia (AML), myelodysplastic syndrome, chronicneutrophilic leukaemia, acute lymphoblastic T cell leukaemia,plasmacytoma, immunoblastic large cell leukaemia, mantle cell leukaemia,multiple myeloma, acute megakaryoblastic leukaemia, acute megakaryocyticleukaemia, promyelocytic leukaemia and erythroleukaemia. Varieties oflymphoma include malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin'slymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicularlymphoma, MALT1 lymphoma and marginal zone lymphoma. Varieties ofnon-haematological malignancy include cancer of the prostate, lung,breast, rectum, colon, lymph node, bladder, kidney, pancreas, liver,ovary, uterus, cervix, brain, skin, bone, stomach and muscle. Modulatorsof TNFα function may also be used to increase the safety of the potentanticancer effect of TNF (see F. V. Hauwermeiren et al., J. Clin.Invest., 2013, 123, 2590-2603).

The present invention also provides a pharmaceutical composition whichcomprises a compound in accordance with the invention as describedabove, or a pharmaceutically acceptable salt or solvate thereof, inassociation with one or more pharmaceutically acceptable carriers.

Pharmaceutical compositions according to the invention may take a formsuitable for oral, buccal, parenteral, nasal, topical, ophthalmic orrectal administration, or a form suitable for administration byinhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets, lozenges or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methyl cellulose); fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogenphosphate); lubricants(e.g. magnesium stearate, talc or silica); disintegrants (e.g. potatostarch or sodium glycollate); or wetting agents (e.g. sodium laurylsulphate). The tablets may be coated by methods well known in the art.Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents,emulsifying agents, non-aqueous vehicles or preservatives. Thepreparations may also contain buffer salts, flavouring agents, colouringagents or sweetening agents, as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of formula (I) may be formulated for parenteraladministration by injection, e.g. by bolus injection or infusion.Formulations for injection may be presented in unit dosage form, e.g. inglass ampoules or multi-dose containers, e.g. glass vials. Thecompositions for injection may take such forms as suspensions, solutionsor emulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilising, preserving and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

In addition to the formulations described above, the compounds offormula (I) may also be formulated as a depot preparation. Suchlong-acting formulations may be administered by implantation or byintramuscular injection.

For nasal administration or administration by inhalation, the compoundsaccording to the present invention may be conveniently delivered in theform of an aerosol spray presentation for pressurised packs or anebuliser, with the use of a suitable propellant, e.g.dichlorodifluoromethane, fluorotrichloromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas ormixture of gases.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack or dispensing device may be accompanied byinstructions for administration.

For topical administration the compounds of use in the present inventionmay be conveniently formulated in a suitable ointment containing theactive component suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Particular carriers include, for example, mineraloil, liquid petroleum, propylene glycol, polyoxyethylene,polyoxypropylene, emulsifying wax and water. Alternatively, thecompounds of use in the present invention may be formulated in asuitable lotion containing the active component suspended or dissolvedin one or more pharmaceutically acceptable carriers. Particular carriersinclude, for example, mineral oil, sorbitan monostearate, polysorbate60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanoland water.

For ophthalmic administration the compounds of use in the presentinvention may be conveniently formulated as micronized suspensions inisotonic, pH-adjusted sterile saline, either with or without apreservative such as a bactericidal or fungicidal agent, for examplephenylmercuric nitrate, benzylalkonium chloride or chlorhexidineacetate. Alternatively, for ophthalmic administration compounds may beformulated in an ointment such as petrolatum.

For rectal administration the compounds of use in the present inventionmay be conveniently formulated as suppositories. These can be preparedby mixing the active component with a suitable non-irritating excipientwhich is solid at room temperature but liquid at rectal temperature andso will melt in the rectum to release the active component. Suchmaterials include, for example, cocoa butter, beeswax and polyethyleneglycols.

The quantity of a compound of use in the invention required for theprophylaxis or treatment of a particular condition will vary dependingon the compound chosen and the condition of the patient to be treated.In general, however, daily dosages may range from around 10 ng/kg to1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01mg/kg to 40 mg/kg body weight, for oral or buccal administration, fromaround 10 ng/kg to 50 mg/kg body weight for parenteral administration,and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg toaround 1000 mg, for nasal administration or administration by inhalationor insufflation.

If desired, a compound in accordance with the present invention may beco-administered with another pharmaceutically active agent, e.g. ananti-inflammatory molecule such as methotrexate or prednisolone.

The compounds of formula (IB-A) above may be prepared by a process whichcomprises reacting a compound of formula Y-E-M¹ with a compound offormula (III):

wherein A, B, D, E, Q, Y, Z and R¹ are as defined above, L¹ represents asuitable leaving group, and M¹ represents a boronic acid moiety —B(OH)₂or a cyclic ester thereof formed with an organic diol, e.g. pinacol,1,3-propanediol or neopentyl glycol, or M¹ represents —ZnHal in whichHal represents a halogen atom, e.g. chloro; in the presence of atransition metal catalyst.

The leaving group L¹ is typically a halogen atom, e.g. chloro or bromo;or an organic sulfonate derivative, e.g. trifluoromethylsulfonate.

The transition metal catalyst of use in the reaction between Y-E-M¹ andcompound (III) is suitably[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloro-[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II),tetrakis(triphenylphosphine)-palladium(0), orbis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethanecomplex. The reaction is suitably performed in the presence of a base,e.g. an inorganic base such as sodium carbonate or potassium carbonate,or potassium phosphate. The reaction is conveniently carried out at anelevated temperature in a suitable solvent, e.g a cyclic ether such as1,4-dioxane or tetrahydrofuran.

Alternatively, the compounds of formula (IB-A) above may be prepared bya variant of the Skraup reaction which comprises reacting a compound offormula (IV) with a compound of formula (V):

wherein A, B, D, E, Q, Y, Z and R¹ are as defined above; in the presenceof a suitable oxidant (cf. Organic Reactions, 1953, 7, 59).

The compounds of formula (IB-B) above may be prepared by a process whichcomprises reacting a compound of formula Y-E-M¹ with a compound offormula (VI):

wherein A, B, D, E, Q, Y, Z, R¹, L¹ and M¹ are as defined above; in thepresence of a transition metal catalyst; under conditions analogous tothose described above for the reaction between Y-E-M¹ and compound(III).

Alternatively, the compounds of formula (IB-B) may be prepared by amethod analogous to that described by C. S. Cho & J. U. Kim, TetrahedronLett., 2007, 48, 3775; or by S. C. Kim, Bull. Korean Chem. Soc., 2005,26, 1001.

The compounds of formula (IB-B) wherein E represents C(O) may beprepared by a method analogous to that described by Y. T. Reddy, Synth.Commun., 2008, 38, 3201.

The compounds of formula (IB-B) wherein -Q-Z represents —NH₂ may beprepared by a method analogous to that described in WO 2007/022946.

The compounds of formula (IB-C) above may be prepared by a process whichcomprises reacting a compound of formula Y-E-M¹ with a compound offormula (VII):

wherein A, B, D, E, Q, Y, Z, R¹, L¹ and M¹ are as defined above; in thepresence of a transition metal catalyst; under conditions analogous tothose described above for the reaction between Y-E-M¹ and compound(III).

The intermediates of formula (VII) wherein L¹ is bromo may be preparedby treating a compound of formula (VIII):

wherein A, B, D, Q, Z and R¹ are as defined above; with a brominatingagent, e.g. N-bromosuccinimide.

The intermediates of formula (VIII) may be prepared by a methodanalogous to that described in WO 2012/148808.

Alternatively, the compounds of formula (IB-C) above may be prepared bya method analogous to that described by D. E. Minter & M. A. Re, J. Org.Chem., 1988, 53, 2653.

The compounds of formula (IB-D) above may be prepared by a process whichcomprises reacting a compound of formula Y-E-M¹ with a compound offormula (IX):

wherein A, B, D, E, Q, Y, Z, R¹, L¹ and M¹ are as defined above; in thepresence of a transition metal catalyst; under conditions analogous tothose described above for the reaction between Y-E-M¹ and compound(III).

Alternatively, the compounds of formula (IB-D) wherein E represents —O—or —S— may be prepared by a process which comprises reacting a compoundof formula (IX) above with a compound of formula Y—OH or Y—SHrespectively, typically in the presence of a base.

The intermediates of formula (IX) may be prepared by a method analogousto that described in WO 2013/003315.

The compounds of formula (IB-E) above may be prepared by a process whichcomprises reacting a compound of formula Y-E-M¹ with a compound offormula (X):

wherein A, B, D, E, Q, Y, Z, R¹, L¹ and M¹ are as defined above; in thepresence of a transition metal catalyst; under conditions analogous tothose described above for the reaction between Y-E-M¹ and compound(III).

Where L¹ represents trifluoromethylsulfonate, the intermediates offormula (X) above may be prepared by reacting a compound of formula(XI):

wherein A, B, D, Q, Z and R¹ are as defined above; with a triflatingagent, e.g. Comins reagent.

The intermediates of formula (XI) may be prepared by a method analogousto that described in U.S. Pat. No. 4,620,000; or in DD 258809.

The compounds of formula (IB-F) above may be prepared by a process whichcomprises reacting a compound of formula Y-E-M¹ with a compound offormula (XII):

wherein A, B, D, E, Y, R¹, L¹ and M¹ are as defined above; in thepresence of a transition metal catalyst; under conditions analogous tothose described above for the reaction between Y-E-M¹ and compound(III).

Alternatively, the compounds of formula (IB-F) wherein E represents —O—or —S— may be prepared by a process which comprises reacting a compoundof formula (XII) above with a compound of formula Y—OH or Y—SHrespectively, typically in the presence of a base.

The intermediates of formula (XII) may be prepared by a method analogousto that described by N. Le Fur et al., Tetrahedron, 2004, 60, 7983.

Alternatively, the compounds of formula (IB-F) wherein E represents C(O)may be prepared by a method analogous to that described by N. A.Al-Awadi, Tetrahedron, 2001, 57, 1609.

The compounds of formula (IB-G) above may be prepared by a process whichcomprises reacting a compound of formula Y-E-M¹ with a compound offormula (XIII):

wherein A, B, D, E, Q, Y, Z, R¹, L¹ and M¹ are as defined above; in thepresence of a transition metal catalyst; under conditions analogous tothose described above for the reaction between Y-E-M¹ and compound(III).

The intermediates of formula (XIII) wherein L¹ is chloro may be preparedby treating a compound of formula (XIV):

wherein A, B, D, Q, Z and R¹ are as defined above; with phosphorusoxychloride.

The intermediates of formula (XIV) may be prepared by reacting acompound of formula Z-Q-CO₂H with a compound of formula (XV):

wherein A, B, D, Q, Z and R¹ are as defined above.

The compounds of formula (IB-H) above may be prepared by a process whichcomprises reacting a compound of formula (XVI) with a compound offormula (XVII):

wherein A, B, D, E, Q, Y, Z and R¹ are as defined above; underconditions analogous to those described by D. Van Leusen & A. M. VanLeusen, Tetrahedron Lett., 1977, 48, 4233.

The intermediates of formula (XVII) above may be prepared by a methodanalogous to that described by J. Ji & K-I. Lee, J. Korean Chem. Soc.,2005, 49, 150.

Alternatively, the compounds of formula (IB-H) above may be prepared bya method analogous to that described in US-A-2005/0176717; or a methodanalogous to that described by A. Kaschers et al., Tetrahedron, 1992,49, 381.

The compounds of formula (IB-H) above may be prepared by a process whichcomprises reacting a compound of formula Y-E-M¹ with a compound offormula (XVIII):

wherein A, B, D, E, Q, Y, Z, R¹, L¹ and M¹ are as defined above; in thepresence of a transition metal catalyst; under conditions analogous tothose described above for the reaction between Y-E-M¹ and compound(III).

The compounds of formula (IB-H) wherein E represents —O— may be preparedby a process which comprises reacting a compound of formula Y—OH with acompound of formula (XVIII) as defined above. The reaction is suitablyperformed in the presence of a base, e.g. an inorganic base such aspotassium carbonate. The reaction is conveniently carried out at anelevated temperature in a suitable solvent, e.g a dialkylsulfoxidederivative such as dimethylsulfoxide.

The compounds of formula (IB-J) above may be prepared by a process whichcomprises reacting a compound of formula Y-E-M¹ with a compound offormula (XIX):

wherein A, B, D, E, Q, Y, Z, R¹, L¹ and M¹ are as defined above; in thepresence of a transition metal catalyst; under conditions analogous tothose described above for the reaction between Y-E-M¹ and compound(III).

The intermediates of formula (XIX) wherein L¹ is chloro may be preparedby treating a compound of formula (XX):

wherein A, B, D, Q, Z and R¹ are as defined above; with phosphorusoxychloride.

The intermediates of formula (XX) may be prepared by reacting hydrazinewith a compound of formula (XXI):

wherein A, B, D, Q, Z and R¹ are as defined above.

The compounds of formula (IB-K) above may be prepared by a process whichcomprises reacting a compound of formula Y-E-M¹ with a compound offormula (XXII):

wherein A, B, D, E, Q, Y, Z, R¹, L¹ and M¹ are as defined above; in thepresence of a transition metal catalyst; under conditions analogous tothose described above for the reaction between Y-E-M¹ and compound(III).

The intermediates of formula (XXII) wherein L¹ is chloro may be preparedby treating a compound of formula (XXIII):

wherein A, B, D, Q, Z and R¹ are as defined above; with phosphorusoxychloride.

The intermediates of formula (XXIII) wherein -Q-Z represents —NH₂ may beprepared by reacting urea with a compound of formula (XXIV):

wherein A, B, D and R¹ are as defined above; under conditions analogousto those described by J. A. Seijas et al., Tetrahedron Lett., 2000, 41,2215.

Alternatively, the compounds of formula (IB-K) above may be prepared bya method analogous to that described by J. Bergman et al., Tetrahedron,1986, 42, 3697.

The compounds of formula (IB-L) above may be prepared by a methodanalogous to that described by R. Cerri, J. Heterocycl. Chem, 1979, 16,1005; or by B. Pal, Magyar Kemiai Folyoirat, 1976, 82, 166.

Alternatively, the compounds of formula (IB-L) above may be prepared bya method analogous to that described by S. Y. Kang, Bull. Korean Chem.Soc., 2011, 32, 2938, commencing from an appropriately substituted fused1,3,4-benzotriazine-4-oxide (prepared as described by K. Pchalek & M. P.Hay, J. Org, Chem., 2006, 71, 6530).

Where they are not commercially available, the starting materials offormula (III), (IV), (V), (VI), (XV), (XVI), (XVIII), (XXI) and (XXIV)may be prepared by standard methods well known from the art.

It will be understood that any compound of formula (I) initiallyobtained from any of the above processes may, where appropriate,subsequently be elaborated into a further compound of formula (I) bytechniques known from the art. By way of example, a compound wherein Erepresents —C(O)— may be converted into the corresponding compoundwherein E represents —CH(OH)— by treatment with a reducing agent such assodium borohydride.

A compound wherein E represents —CH(OH)— may be converted into thecorresponding compound wherein E represents —CH₂— by heating withelemental iodine and phosphinic acid in acetic acid; or by treating withtriethylsilane and an acid, e.g. an organic acid such as trifluoroaceticacid, or a Lewis acid such as boron trifluoride diethyl etherate; or bytreating with chlorotrimethylsilane and sodium iodide; or by a two-stepprocedure which comprises: (i) treatment with thionyl bromide; and (ii)treatment of the product thereby obtained with a transition metalcatalyst, e.g. (2,2′-bipyridine)dichloro-ruthenium(II) hydrate, in thepresence of diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylate(Hantzsch ester) and a base, e.g. an organic base such asN,N-diisopropylethylamine.

A compound wherein E represents —CH₂— may be converted into thecorresponding compound wherein E represents —CH(CH₃)— by treatment witha methyl halide, e.g. methyl iodide, in the presence of a base such aslithium hexamethyldisilazide.

A compound which contains a hydroxy group may be alkylated by treatmentwith the appropriate alkyl halide in the presence of a base, e.g. sodiumhydride, or silver oxide. A compound which contains hydroxy may beconverted into the corresponding fluoro-substituted compound bytreatment with diethylaminosulfur trifluoride (DAST) orbis(2-methoxyethyl)aminosulfur trifluoride (BAST). A compound whichcontains hydroxy may be converted into the correspondingdifluoro-substituted compound via a two-step procedure which comprises:(i) treatment with an oxidising agent, e.g. manganese dioxide; and (ii)treatment of the carbonyl-containing compound thereby obtained withDAST.

A compound which contains an N—H moiety may be alkylated by treatmentwith the appropriate alkyl halide, typically at an elevated temperaturein an organic solvent such as acetonitrile; or at ambient temperature inthe presence of a base, e.g. an alkali metal carbonate such as potassiumcarbonate or cesium carbonate, in a suitable solvent, e.g. a dipolaraprotic solvent such as N,N-dimethylformamide. Alternatively, a compoundwhich contains an N—H moiety may be alkylated by treatment with theappropriate alkyl tosylate in the presence of a base, e.g. an inorganicbase such as sodium hydride, or an organic base such as1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

A compound which contains an N—H moiety may be methylated by treatmentwith formaldehyde in the presence of a reducing agent, e.g. sodiumtriacetoxyborohydride.

A compound which contains an N—H moiety may be acylated by treatmentwith the appropriate acid chloride, e.g. acetyl chloride, or with theappropriate carboxylic acid anhydride, e.g. acetic anhydride, typicallyat ambient temperature in the presence of a base, e.g. an organic basesuch as triethylamine.

A compound which contains an N—H moiety may be converted into thecorresponding compound wherein the nitrogen atom is substituted by C₁₋₆alkylsulphonyl, e.g. methylsulphonyl, by treatment with the appropriateC₁₋₆ alkylsulphonyl chloride, e.g. methanesulphonyl chloride, or withthe appropriate C₁₋₆ alkylsulphonic acid anhydride, e.g.methanesulphonic anhydride, typically at ambient temperature in thepresence of a base, e.g. an organic base such as triethylamine orN,N-diisopropylethylamine.

A compound substituted by amino (—NH₂) may be converted into thecorresponding compound substituted by C₁₋₆ alkylsulphonylamino, e.g.methylsulphonylamino, or bis[(C₁₋₆)alkylsulphonyl]amino, e.g.bis(methylsulphonyl)amino, by treatment with the appropriate C₁₋₆alkylsulphonyl halide, e.g. a C₁₋₆ alkylsulphonyl chloride such asmethanesulphonyl chloride. Similarly, a compound substituted by hydroxy(—OH) may be converted into the corresponding compound substituted byC₁₋₆ alkylsulphonyloxy, e.g. methylsulphonyloxy, by treatment with theappropriate C₁₋₆ alkylsulphonyl halide, e.g. a C₁₋₆ alkylsulphonylchloride such as methanesulphonyl chloride.

A compound containing the moiety —S— may be converted into thecorresponding compound containing the moiety —S(O)— by treatment with3-chloroperoxybenzoic acid. Likewise, a compound containing the moiety—S(O)— may be converted into the corresponding compound containing themoiety —S(O)₂— by treatment with 3-chloroperoxybenzoic acid.Alternatively, a compound containing the moiety —S— may be convertedinto the corresponding compound containing the moiety —S(O)₂— bytreatment with Oxone® (potassium peroxymonosulfate).

A compound containing an aromatic nitrogen atom may be converted intothe corresponding N-oxide derivative by treatment with3-chloroperoxybenzoic acid.

A bromophenyl derivative may be converted into the correspondingoptionally substituted 2-oxopyrrolidin-1-ylphenyl or2-oxooxazolidin-3-ylphenyl derivative by treatment with pyrrolidin-2-oneor oxazolidin-2-one, or an appropriately substituted analogue thereof.The reaction is conveniently effected at an elevated temperature in thepresence of copper(I) iodide, trans-N,N′-dimethylcyclohexane-1,2-diamineand an inorganic base such as potassium carbonate.

A compound wherein R¹ represents halogen, e.g. chloro, bromo or iodo,may be converted into the corresponding compound wherein R¹ representsan optionally substituted aryl or heteroaryl moiety by treatment withthe appropriately substituted aryl or heteroaryl boronic acid or acyclic ester thereof formed with an organic diol, e.g. pinacol,1,3-propanediol or neopentyl glycol. The reaction is typically effectedin the presence of a transition metal catalyst, e.g.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),tetrakis(triphenylphosphine)palladium(0), orbis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethanecomplex, or dichlorobis(triphenyl-phosphine)palladium(II), and a base,e.g. an inorganic base such as sodium carbonate or potassium carbonate,or potassium phosphate.

A compound wherein R¹ represents halogen, e.g. bromo, may be convertedinto the corresponding compound wherein R¹ represents an optionallysubstituted aryl, heteroaryl or heterocycloalkenyl moiety via a two-stepprocedure which comprises: (i) reaction with bis(pinacolato)diboron orbis(neopentyl glycolato)diboron; and (ii) reaction of the compoundthereby obtained with an appropriately functionalised halo- ortosyloxy-substituted aryl, heteroaryl or heterocycloalkenyl derivative.Step (i) is conveniently effected in the presence of a transition metalcatalyst such as[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), orbis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethanecomplex. Step (ii) is conveniently effected in the presence of atransition metal catalyst such astetrakis(triphenylphosphine)-palladium(0), orbis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethanecomplex, and a base, e.g. an inorganic base such as sodium carbonate orpotassium carbonate.

A compound wherein R¹ represents halogen, e.g. bromo, may be convertedinto the corresponding compound wherein R¹ represents an optionallysubstituted C₂₋₆ alkynyl moiety by treatment with an appropriatelysubstituted alkyne derivative, e.g. 2-hydroxybut-3-yne. The reaction isconveniently accomplished with the assistance of a transition metalcatalyst, e.g. tetrakis(triphenylphosphine)palladium(0), typically inthe presence of copper(I) iodide and a base, e.g. an organic base suchas triethylamine.

A compound wherein R¹ represents halogen, e.g. bromo, may be convertedinto the corresponding compound wherein R¹ represents an optionallysubstituted imidazol-1-yl moiety by treatment with the appropriatelysubstituted imidazole derivative, typically in the presence ofcopper(II) acetate and an organic base such asN,N,N′,N′-tetramethyl-ethylenediamine (TMEDA).

A compound wherein R¹ represents halogen, e.g. bromo, may be convertedinto the corresponding compound wherein R¹ represents2-(methoxycarbonyl)ethyl via a two-step procedure which comprises: (i)reaction with methyl acrylate; and (ii) catalytic hydrogenation of thealkenyl derivative thereby obtained, typically by treatment with ahydrogenation catalyst, e.g. palladium on charcoal, under an atmosphereof hydrogen gas. Step (i) is typically effected in the presence of atransition metal catalyst, e.g. palladium(II) acetate orbis(dibenzylideneacetone)palladium(0), and a reagent such astri(ortho-tolyl)-phosphine.

In general, a compound containing a —C═C— functionality may be convertedinto the corresponding compound containing a —CH—CH— functionality bycatalytic hydrogenation, typically by treatment with a hydrogenationcatalyst, e.g. palladium on charcoal, under an atmosphere of hydrogengas, optionally in the presence of a base, e.g. an alkali metalhydroxide such as sodium hydroxide, or an organic base such astriethylamine.

A compound wherein R¹ represents 6-methoxypyridin-3-yl may be convertedinto the corresponding compound wherein R¹ represents2-oxo-1,2-dihydropyridin-5-yl by treatment with pyridine hydrochloride;or by heating with a mineral acid such as hydrochloric acid. Byutilising similar methodology, a compound wherein R¹ represents6-methoxy-4-methylpyridin-3-yl may be converted into the correspondingcompound wherein R¹ represents 4-methyl-2-oxo-1,2-dihydropyridin-5-yl;and a compound wherein R¹ represents 6-methoxy-5-methylpyridin-3-yl maybe converted into the corresponding compound wherein R¹ represents3-methyl-2-oxo-1,2-dihydropyridin-5-yl.

A compound wherein R¹ represents 2-oxo-1,2-dihydropyridin-5-yl may beconverted into the corresponding compound wherein R¹ represents2-oxopiperidin-5-yl by catalytic hydrogenation, typically by treatmentwith gaseous hydrogen in the presence of a hydrogenation catalyst suchas platinum(IV) oxide.

A compound containing an ester moiety, e.g. a C₂₋₆ alkoxycarbonyl groupsuch as methoxycarbonyl or ethoxycarbonyl, may be converted into thecorresponding compound containing a carboxy (—CO₂H) moiety by treatmentwith an acid, e.g. a mineral acid such as hydrochloric acid.

A compound containing an N-(tert-butoxycarbonyl) moiety may be convertedinto the corresponding compound containing an N—H moiety by treatmentwith an acid, e.g. a mineral acid such as hydrochloric acid, or anorganic acid such as trifluoroacetic acid.

A compound containing an ester moiety, e.g. a C₂₋₆ alkoxycarbonyl groupsuch as methoxycarbonyl or ethoxycarbonyl, may alternatively beconverted into the corresponding compound containing a carboxy (—CO₂H)moiety by treatment with a base, e.g. an alkali metal hydroxide selectedfrom lithium hydroxide, sodium hydroxide and potassium hydroxide; or anorganic base such as sodium methoxide or sodium ethoxide.

A compound containing a carboxy (—CO₂H) moiety may be converted into thecorresponding compound containing an amide moiety by treatment with theappropriate amine in the presence of a condensing agent such as1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, or a coupling agent suchas 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU).

A compound containing a carbonyl (C═O) moiety may be converted into thecorresponding compound containing a —C(CH₃)(OH)— moiety by treatmentwith methylmagnesium bromide. Similarly, a compound containing acarbonyl (C═O) moiety may be converted into the corresponding compoundcontaining a —C(CF₃)(OH)— moiety by treatment with(trifluoromethyl)trimethylsilane and cesium fluoride. A compoundcontaining a carbonyl (C═O) moiety may be converted into thecorresponding compound containing a —C(CH₂NO₂)(OH)— moiety by treatmentwith nitromethane.

A compound containing a hydroxymethyl moiety may be converted into thecorresponding compound containing a formyl (—CHO) moiety by treatmentwith an oxidising agent such as Dess-Martin periodinane. A compoundcontaining a hydroxymethyl moiety may be converted into thecorresponding compound containing a carboxy moiety by treatment with anoxidising agent such as tetrapropylammonium perruthenate. Similarly, acompound containing a —CH(OH)— moiety may be converted into thecorresponding compound containing a —C(O)— moiety by treatment with anoxidising agent such as tetrapropylammonium perruthenate.

A compound wherein R¹ represents a substituent containing at least onenitrogen atom, which substituent is linked to the remainder of themolecule via a nitrogen atom, may be prepared by reacting a compoundwherein R¹ represents halogen, e.g. bromo, with the appropriate compoundof formula R¹—H [e.g. 1-(pyridin-3-yl)piperazine or morpholine]. Thereaction is conveniently effected with the assistance of a transitionmetal catalyst, e.g. tris(dibenzylideneacetone)dipalladium(0), in thepresence of an amination ligand such as2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) or2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP) and a base, e.g.an inorganic base such as sodium tert-butoxide. Alternatively, thereaction may be effected using palladium diacetate, in the presence of areagent such as[2′,6′-bis(propan-2-yloxy)-biphenyl-2-yl](dicyclohexyl)phosphane and abase, e.g. an inorganic base such as cesium carbonate.

A compound containing an oxo moiety can be converted into thecorresponding compound containing an ethoxycarbonylmethylidene moiety bytreatment with triethyl phosphonoacetate in the presence of a base suchas sodium hydride.

A compound wherein R²¹ represents ethenyl may be prepared by reacting acompound wherein R²¹ represents halogen, e.g. chloro, with potassiumvinyl trifluoro-borate. The reaction is typically effected in thepresence of a transition metal catalyst, e.g.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and a base,e.g. an organic base such as triethylamine.

A compound wherein R²¹ represents halogen, e.g. chloro, may be convertedinto the corresponding compound wherein R²¹ represents an optionallysubstituted C₄₋₇ cycloalkenyl moiety by treatment with the appropriatelysubstituted cycloalkenyl boronic acid or a cyclic ester thereof formedwith an organic diol, e.g. pinacol, 1,3-propanediol or neopentyl glycol.The reaction is typically effected in the presence of a transition metalcatalyst, e.g.bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethanecomplex, and a base, e.g. an inorganic base such as potassium carbonate.

A compound wherein R²¹ represents a substituent containing at least onenitrogen atom, which substituent is linked to the remainder of themolecule via a nitrogen atom, may be prepared by reacting a compoundwherein R²¹ represents halogen, e.g. chloro, with the appropriatecompound of formula R²¹—H [e.g. 2-methoxyethylamine, N-methyl-L-alanine,2-aminocyclopentanecarboxylic acid, 3-aminocyclopentanecarboxylic acid,1-(aminomethyl)cyclopropanecarboxylic acid, methylazetidine-3-carboxylate, pyrrolidin-3-ol, pyrrolidine-3-carboxylic acid,piperidine-2-carboxylic acid, piperidine-3-carboxylic acid,4-(1H-tetrazol-5-yl)piperidine, piperazine,1-(methylsulfonyl)piperazine, piperazin-2-one,2-(piperazin-1-yl)propanoic acid, morpholine, morpholine-2-carboxylicacid, thiomorpholine, thiomorpholine 1,1-dioxide, 1,4-diazepan-5-one,2-oxa-5-azabicyclo-[2.2.1]heptane or an appropriately substitutedazaspiroalkane], optionally in the presence of a base, e.g. an organicbase such as triethylamine or N,N-diisopropylethylamine and/or1-methyl-2-pyrrolidinone, or pyridine, or an inorganic base such aspotassium carbonate.

Where a mixture of products is obtained from any of the processesdescribed above for the preparation of compounds according to theinvention, the desired product can be separated therefrom at anappropriate stage by conventional methods such as preparative HPLC; orcolumn chromatography utilising, for example, silica and/or alumina inconjunction with an appropriate solvent system.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques. In particular,where it is desired to obtain a particular enantiomer of a compound offormula (I), this may be produced from a corresponding mixture ofenantiomers using any suitable conventional procedure for resolvingenantiomers. Thus, for example, diastereomeric derivatives, e.g. salts,may be produced by reaction of a mixture of enantiomers of formula (I),e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base.The diastereomers may then be separated by any convenient means, forexample by crystallisation, and the desired enantiomer recovered, e.g.by treatment with an acid in the instance where the diastereomer is asalt. In another resolution process a racemate of formula (I) may beseparated using chiral HPLC. Moreover, if desired, a particularenantiomer may be obtained by using an appropriate chiral intermediatein one of the processes described above. Alternatively, a particularenantiomer may be obtained by performing an enantiomer-specificenzymatic biotransformation, e.g. an ester hydrolysis using an esterase,and then purifying only the enantiomerically pure hydrolysed acid fromthe unreacted ester antipode.

Chromatography, recrystallisation and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular geometric isomer of the invention.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 3^(rd) edition, 1999. The protecting groups may be removedat any convenient subsequent stage utilising methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

The compounds in accordance with this invention potently inhibit thebinding of a fluorescence conjugate to TNFα when tested in thefluorescence polarisation assay described below. Moreover, certaincompounds in accordance with this invention potently inhibitTNFα-induced NF-κB activation in the reporter gene assay describedbelow.

Fluorescence Polarisation Assay

Preparation of Compound (A)

1-(2,5-Dimethylbenzyl)-6-[4-(piperazin-1-ylmethyl)phenyl]-2-(pyridin-4-ylmethyl)-1H-benzimidazole—hereinafterreferred to as “Compound (A)”—can be prepared by the procedure describedin Example 499 of WO 2013/186229; or by a procedure analogous thereto.

Preparation of Fluorescence Conjugate

Compound (A)

(27.02 mg, 0.0538 mmol) was dissolved in DMSO (2 mL). 5(-6)Carboxy-fluorescein succinimyl ester (24.16 mg, 0.0510 mmol) (Invitrogencatalogue number: C1311) was dissolved in DMSO (1 mL) to give a brightyellow solution. The two solutions were mixed at room temperature, themixture turning red in colour. The mixture was stirred at roomtemperature. Shortly after mixing a 20 μL aliquot was removed anddiluted in a 80:20 mixture of AcOH:H₂O for LC-MS analysis on the1200RR-6140 LC-MS system. The chromatogram showed two closely elutingpeaks at retention times of 1.42 and 1.50 minutes, both with mass(M+H)⁺=860.8 amu, corresponding to the two products formed with the 5-and 6-substituted carboxyfluorescein group. A further peak at retentiontime 2.21 minutes had a mass of (M+H)⁺=502.8 amu, corresponding toCompound (A). No peak was observed for unreacted 5(-6)carboxyfluorescein succinimyl ester. The peak areas were 22.0%, 39.6%and 31.4% for the three signals, indicating a 61.6% conversion to thetwo isomers of the desired fluorescence conjugate at that time-point.Further 20 μL aliquots were extracted after several hours and then afterovernight stirring, diluted as before and subjected to LC-MS analysis.The percentage conversion was determined as 79.8% and 88.6% respectivelyat these time-points. The mixture was purified on a UV-directedpreparative HPLC system. The pooled purified fractions were freeze-driedto remove excess solvent. After freeze-drying, an orange solid (23.3 mg)was recovered, equivalent to 0.027 mmol of fluorescence conjugate,corresponding to an overall yield of 53% for the reaction andpreparative HPLC purification.

Inhibition of Binding of Fluorescence Conjugate to TNFα

Compounds were tested at 10 concentrations starting from 25 μM in afinal assay concentration of 5% DMSO, by pre-incubation with TNFα for 60minutes at ambient temperature in 20 mM Tris, 150 mM NaCl, 0.05% Tween20, before addition of the fluorescence conjugate and a furtherincubation for 20 hours at ambient temperature. The final concentrationsof TNFα and the fluorescence conjugate were 10 nM and 10 nM respectivelyin a total assay volume of 25 pt. Plates were read on a plate readercapable of detecting fluorescence polarisation (e.g. an Analyst HT platereader; or an Envision plate reader). An IC₅₀ value was calculated usingXLfit™ (4 parameter logistic model) in ActivityBase.

When tested in the fluorescence polarisation assay, the compounds of theaccompanying Examples were all found to exhibit IC₅₀ values of 50 μM orbetter.

Reporter Gene Assay

Inhibition of TNFα-Induced NF-κB Activation

Stimulation of HEK-293 cells by TNFα leads to activation of the NF-κBpathway. The reporter cell line used to determine TNFα activity waspurchased from InvivoGen. HEK-Blue™ CD40L is a stable HEK-293transfected cell line expressing SEAP (secreted embryonic alkalinephosphatase) under the control of the IFNβ minimal promoter fused tofive NF-κB binding sites. Secretion of SEAP by these cells is stimulatedin a dose-dependent manner by TNFα, with an EC50 of 0.5 ng/mL for humanTNFα. Compounds were diluted from 10 mM DMSO stocks (final assayconcentration 0.3% DMSO) to generate a 10-point 3-fold serial dilutioncurve (e.g. 30,000 nM to 2 nM final concentration). Diluted compound waspreincubated with TNFα for 60 minutes prior to addition to a 384-wellmicrotitre plate and incubated for 18 h. The final TNFα concentration inthe assay plate was 0.5 ng/mL. SEAP activity was determined in thesupernatant using a colorimetric substrate, e.g. QUANTI-Blue™ orHEK-Blue® Detection media (InvivoGen). Percentage inhibitions forcompound dilutions were calculated between a DMSO control and maximuminhibition (by excess control compound) and an IC₅₀ value calculatedusing XLfit™ (4 parameter logistic model) in ActivityBase.

When tested in the reporter gene assay, certain compounds of theaccompanying Examples were found to exhibit IC₅₀ values of 50 μM orbetter.

EXAMPLES Abbreviations

DCM: dichloromethane EtOAc: ethyl acetate

MeOH: methanol DMSO: dimethylsulfoxide

DMF: N,N-dimethylformamide THF: tetrahydrofuran

Pd(dppf)Cl₂: [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

Barluenga's Reagent: bis(pyridine)iodonium(I) tetrafluoroborate

h: hour M: mass

r.t. room temperature RT: retention time

HPLC: High Performance Liquid Chromatography

LCMS: Liquid Chromatography Mass Spectrometry

ES+: Electrospray Positive Ionisation

Nomenclature

Compounds were named with the aid of ACD/Name Batch (Network) version12.0 and/or Accelrys Draw 4.0.

Analytical Conditions

All reactions involving air- or moisture-sensitive reagents wereperformed under a nitrogen atmosphere using dried solvents andglassware.

LCMS data were determined by using Method 1 below.

Method 1

Column: Waters Acquity-SQD, Waters Acquity UPLC, BEH C18, 2.1×50 mm, 1.7μm

Mobile phase A: 10 mM ammonium formate+0.1% ammonia

Mobile phase B: 95% acetonitrile+5% water+0.1% ammonia

Gradient program (flow rate 1.0 mL/minute, column temperature 40° C.):

Time A % B % 0.00 95.0 5.0 0.50 95.0 5.0 1.75 5.0 95.0 2.00 5.0 95.02.25 95.0 5.0

Intermediate 1 1-(2-Aminophenyl)propan-1-one

To a cooled (0° C.) solution of 2-aminobenzonitrile (5 g, 42.3 mmol) inTHF (20 mL) was added dropwise ethylmagnesium chloride (2M in THF, 52.9mL, 105.8 mmol) over 30 minutes via an addition funnel. The reactionmixture was allowed to warm to r.t. and stirred for 6 h. The reactionmixture was cooled to 0° C. and quenched by careful addition of 2Maqueous hydrochloric acid solution (ca. 60 mL). After 10 minutes, themixture was basified at 0° C. by the slow addition of 2M aqueous sodiumhydroxide solution (ca. 60 mL). The mixture was extracted with EtOAc(3×100 mL). The combined organic layers were dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by flash columnchromatography (SiO₂, 0-25% EtOAc/heptane), yielding the title compound(2.91 g, 46%) as a yellow oil which crystallised upon standing. δ_(H)(250 MHz, CDCl₃) 7.77 (dd, J 8.5, 1.5 Hz, 1H), 7.42-7.12 (m, 1H),6.71-6.62 (m, 2H), 6.28 (br s, 2H), 3.00 (q, J 7.5 Hz, 2H), 1.23 (t, J7.5 Hz, 3H). LCMS (ES⁺) 151.0 (M+H)⁺, RT 1.12 minutes.

Intermediate 2 N-(2-Propanoylphenyl)acetamide

To a solution of Intermediate 1 (2.91 g, 19.5 mmol) in DCM (80 mL) wasadded triethylamine (2.99 mL, 21.5 mmol), followed by acetyl chloride(1.66 mL, 23.4 mmol). The reaction mixture was stirred at r.t. for 3 h,then washed with water (100 mL). The aqueous layer was back-extractedwith DCM (2×50 mL). The combined organic layers were dried (Na₂SO₄) andconcentrated in vacuo, yielding the title compound (3.72 g, 99%) as apale yellow solid, which was used without further purification. δ_(H)(500 MHz, CDCl₃) 11.75 (s, 1H), 8.74 (dd, J 8.5, 1.0 Hz, 1H), 7.93 (dd,J 8.0, 1.5 Hz, 1H), 7.58-7.51 (m, 1H), 7.15-7.08 (m, 1H), 3.08 (q, J 7.0Hz, 2H), 2.24 (s, 3H), 1.23 (t, J 7.0 Hz, 3H). LCMS (ES⁺) 192.0 (M+H)⁺,RT 1.11 minutes.

Intermediate 3 N-(4-Bromo-2-propanoylphenyl)acetamide

To a solution of Intermediate 2 (3.72 g, 19.5 mmol) in acetic acid (40mL) was added bromine (1.61 mL, 31.3 mmol) dropwise. The reactionmixture was stirred at r.t. for 1.5 h, then poured into water (80 mL).The resultant precipitate was collected by filtration, washed with water(50 mL) and heptane (50 mL), then dried in a vacuum oven at 40° C. for18 h, yielding the title compound (4.82 g, 84%) as a pale yellow solid,which was used without further purification. δ_(H) (500 MHz, CDCl₃)11.63 (s, 1H), 8.68 (d, J 9.0 Hz, 1H), 8.02 (d, J 2.5 Hz, 1H), 7.63 (dd,J 9.0, 2.5 Hz, 1H), 3.05 (q, J 7.0 Hz, 2H), 2.24 (s, 3H), 1.23 (t, J 7.0Hz, 3H). LCMS (ES⁺) 270.0/272.0 (M+H)⁺, RT 1.26 minutes.

Intermediate 4 6-Bromo-3-methyl-1H-cinnolin-4-one

To a solution of Intermediate 3 (4.82 g, 16.3 mmol) in THF (55 mL) wereadded conc. HCl (12 mL) and water (12 mL) and the resultant slurry washeated at 75° C. for 1.5 h. The reaction mixture was cooled to r.t. andthe organic solvent was removed in vacuo. The resultant aqueoussuspension was diluted with water (4 mL) and conc. HCl (4 mL), thencooled to −5° C. A solution of sodium nitrite (1.36 g, 19.5 mmol) inwater (8 mL) was added in five portions, maintaining a reactiontemperature below 0° C. The reaction mixture was warmed slowly to r.t.over 2 h, then stirred at r.t. for 18 h. After this time, the reactionmixture was heated at reflux for 6 h, then cooled to r.t. and filtered.The resultant solid was washed with water (2×20 mL) and diethyl ether(30 mL), then dried in a vacuum oven at 40° C. for 18 h, yielding thetitle compound (3.23 g, 83%) as a beige solid, which was used withoutfurther purification. δ_(H) (500 MHz, CDCl₃) 13.35 (s, 1H), 8.13 (d, J2.0 Hz, 1H), 7.88 (dd, J 9.0, 2.0 Hz, 1H), 7.54 (d, J 9.0 Hz, 1H), 2.27(s, 3H). LCMS (ES⁺) 239.0/241.0 (M+H)⁺, RT 0.99 minutes.

Intermediate 5 3-Methyl-6-[4-(methylsulfonyl)phenyl]-1H-cinnolin-4-one

A mixture of Intermediate 4 (500 mg, 1.97 mmol) and4-(methylsulfonyl)phenyl-boronic acid (433 mg, 2.16 mmol) in 1,4-dioxane(30 mL) and 2M aqueous potassium carbonate solution (2.95 mL, 5.90 mmol)was degassed for 10 minutes under a stream of nitrogen prior to theaddition of Pd(dppf)Cl₂.DCM (161 mg, 0.2 mmol). The reaction mixture washeated at 100° C. for 1 h. The reaction mixture was cooled to r.t, thenpartitioned between water (100 mL) and EtOAc (100 mL). The resultantprecipitate between the layers was collected by filtration and dried ina vacuum oven at 40° C. for 18 h, yielding the title compound (484 mg,78%) as a grey solid. δ_(H) (500 MHz, DMSO-d₆) 8.36 (d, J 2.0 Hz, 1H),8.13 (dd, J 9.0, 2.0 Hz, 1H), 8.04 (s, 4H), 7.71 (d, J 9.0 Hz, 1H), 3.27(s, 3H), 2.31 (s, 3H). LCMS (ES⁺) 315.0 (M+H)⁺, RT 1.02 minutes.

Intermediate 6 4-Chloro-3-methyl-6-[4-(methylsulfonyl)phenyl]cinnoline

A solution of Intermediate 5 (200 mg, 0.64 mmol) in phosphorustrichloride (1.48 mL, 15.9 mmol) was heated at 100° C. for 2 h. Thereaction mixture was poured onto ice (20 mL) and the pH was adjusted toca. pH 5 by the addition of 6M aqueous sodium hydroxide solution, thenthe mixture was extracted with EtOAc (3×20 mL). The combined organiclayers were washed with brine (20 mL), then dried (Na₂SO₄) andconcentrated in vacuo, yielding the title compound (223 mg,quantitative) as a dark purple solid, which was used without furtherpurification. δ_(H) (500 MHz, DMSO-d₆) 8.67 (d, J 9.0 Hz, 1H), 8.45 (s,1H), 8.39 (d, J 9.0 Hz, 1H), 8.27-8.08 (m, 4H), 3.02 (s, 3H). LCMS (ES⁺)332.9/334.8 (M+H)⁺, RT 1.16 minutes.

Intermediates 7 & 8 6-Bromo-4-chloro-3-methylcinnoline and4,6-Dichloro-3-methylcinnoline

A solution of Intermediate 4 (400 mg, 1.57 mmol) in phosphorustrichloride (2.49 mL, 26.7 mmol) was heated at 100° C. for 2 h. Thereaction mixture was poured onto ice (20 mL) and the pH was adjusted toca. pH 5 by the addition of 6M aqueous sodium hydroxide solution, thenthe mixture was extracted with EtOAc (3×20 mL). The combined organiclayers were washed with brine (20 mL), then dried (Na₂SO₄) andconcentrated in vacuo, yielding a 65:35 inseparable mixture of the titlecompounds (366 mg, 59%) as a grey solid, which was used without furtherpurification. δ_(H) (500 MHz, DMSO-d₆) 8.46 (d, J 9.0 Hz, 1H), 8.37 (d,J 2.0 Hz, 1H), 8.12 (dd, J 9.0, 2.0 Hz, 1H), 2.98 (s, 3H). LCMS (ES⁺)256.8/258.0 (M+H)⁺, RT 1.28 minutes; and 212.9/214.9 (M+H)⁺ RT 1.25minutes.

Intermediate 92-[5-(4-Chloro-3-methylcinnolin-6-yl)pyrimidin-2-yl]propan-2-ol

A solution of a 65:35 mixture of Intermediates 7 and 8 (366 mg, 0.92mmol) and2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol(245 mg, 0.93 mmol) in 1,4-dioxane (10 mL) and 2M aqueous potassiumcarbonate solution (1.39 mL, 2.78 mmol) was degassed for 10 minutesunder a stream of nitrogen prior to the addition of Pd(dppf)Cl₂.DCM (38mg, 0.05 mmol). The reaction mixture was heated at 70° C. for 2 h. Thereaction mixture was cooled to r.t, diluted with water (25 mL) andextracted with DCM (3×25 mL). The combined organic layers were dried(Na₂SO₄) and concentrated in vacuo. The residue was purified by flashcolumn chromatography (SiO₂, 0-100% EtOAc/heptane), yielding the titlecompound (223 mg, 77%) as a yellow solid. δ_(H) (500 MHz, DMSO-d₆) 9.37(s, 2H), 8.67 (d, J 9.0 Hz, 1H), 8.54 (d, J 2.0 Hz, 1H), 8.43 (dd, J9.0, 2.0 Hz, 1H), 5.19 (s, 1H), 3.01 (s, 3H), 1.58 (s, 6H). LCMS (ES⁺)315.0/317.0 (M+H)⁺, RT 1.08 minutes.

Intermediate 10 6-Chloro-3-methyl-4-(2-methylphenoxy)cinnoline

To a cooled (0° C.) solution of 2-methylphenol (44 μL, 0.43 mmol) in DMF(3 mL) was added sodium hydride (60% suspension in mineral oil, 20 mg,0.51 mmol). The reaction mixture was stirred at 0° C. for 15 minutes,prior to the addition of Intermediate 8 (90 mg, 0.39 mmol) in DMF (1mL). The reaction mixture was stirred at r.t. for 5 h, then quenched bythe addition of water (5 mL), further diluted with water (20 mL) andextracted with EtOAc (3×25 mL). The combined organic layers were washedwith brine (30 mL), dried (Na₂SO₄) and concentrated in vacuo. Theresultant crude material was purified by flash column chromatography(SiO₂, 0-50% EtOAc/heptane), yielding the title compound (91 mg, 77%) asa pale yellow solid. δ_(H) (250 MHz, CDCl₃) 8.50 (d, J 9.0 Hz, 1H), 7.88(d, J 2.0 Hz, 1H), 7.72 (dd, J 9.0, 2.0 Hz, 1H), 7.40-7.30 (m, 1H),7.10-6.94 (m, 2H), 6.23-6.11 (m, 1H), 2.70 (s, 3H), 2.53 (s, 3H). LCMS(ES⁺) 284.9/287.0 (M+H)⁺, RT 1.45 minutes.

Intermediate 11 2-Chloro-4-[4-(methanesulfonyl)phenyl]benzaldehyde

A mixture of 4-bromo-2-chlorobenzaldehyde (5.00 g, 22.8 mmol) and4-(methanesulfonylphenyl)boronic acid (4.56 g, 22.8 mmol) in 1,4-dioxane(100 mL) and 2M aqueous sodium carbonate solution (34.6 mL, 69.2 mmol)was degassed for 10 minutes under a stream of nitrogen prior to theaddition of Pd(dppf)Cl₂.DCM (930 mg, 1.14 mmol). The reaction mixturewas heated at 80° C. for 2 h. The reaction mixture was cooled to r.t.,diluted with water (50 mL) and extracted with EtOAc (3×50 mL). Thecombined organic layers were washed with brine (50 mL), dried (MgSO₄)and concentrated in vacuo. The resulting material was purified by flashcolumn chromatography (SiO₂, 30-100% EtOAc/heptane), yielding the titlecompound (4.0 g, 58%) as an orange solid. δ_(H) (500 MHz, CDCl₃) 10.53(d, J 1.0 Hz, 1H), 8.09-8.02 (m, 3H), 7.82-7.78 (m, 2H), 7.70 (d, J 1.5Hz, 1H), 7.64-7.61 (m, 1H), 3.11 (s, 3H).

Intermediate 12 4-[4-(Methylsulfonyl)phenyl]-2-(prop-1-ynyl)benzaldehyde

A solution of Intermediate 11 (2.61 g, 8.77 mmol) in toluene (60 mL) wasdegassed for 10 minutes under a stream of nitrogen prior to the additionof tetrakis-(triphenylphosphine)palladium(0) (486 mg, 0.42 mmol),followed by tributyl(1-propynyl)tin (4.00 mL, 13.2 mmol). The reactionmixture was heated at 110° C. for 5 h. The reaction mixture was cooledto r.t., then poured into saturated aqueous potassium fluoride solution(100 mL) and extracted with EtOAc (3×75 mL). The combined organic layerswere washed with brine (75 mL), dried (MgSO₄) and concentrated in vacuo.The residue was purified by flash column chromatography (SiO₂, 20-100%EtOAc/heptane), yielding the title compound (3.06 g, 52%) as anoff-white solid. δ_(H) (500 MHz, CDCl₃) 10.56 (d, J 1.0 Hz, 1H),8.07-8.03 (m, 2H), 8.00 (d, J 8.0 Hz, 1H), 7.82-7.78 (m, 2H), 7.75 (d, J2.0 Hz, 1H), 7.62 (dd, J 8.0, 1.0 Hz, 1H), 3.11 (s, 3H), 2.17 (s, 3H).LCMS (ES⁺) 299.0 (M+H)⁺, RT 1.63 minutes.

Intermediate 13{4-[4-(Methylsulfonyl)phenyl]-2-(prop-1-ynyl)phenyl}methanol

To a cooled (0° C.) suspension of Intermediate 12 (2.56 g, 8.58 mmol) inTHF (30 mL) and MeOH (30 mL) was added sodium borohydride (649 mg, 17.2mmol) portionwise. The reaction mixture was allowed to warm to r.t. over1 h, then quenched with water (15 mL). The organic solvents were removedin vacuo. The resultant mixture was extracted with EtOAc (3×15 mL). Thecombined organic layers were washed with water (15 mL), then dried(MgSO₄) and concentrated in vacuo, yielding the title compound (2.59 g,85%) as an off-white solid, which was used without further purification.δ_(H) (500 MHz, CDCl₃) 8.02-7.98 (m, 2H), 7.77-7.74 (m, 2H), 7.66 (s,1H), 7.55-7.51 (m, 2H), 4.86 (d, J 6.5 Hz, 2H), 3.09 (s, 3H), 2.13 (s,3H).

Intermediate 141-(Azidomethyl)-4-[4-(methanesulfonyl)phenyl]-2-(prop-1-yn-1-yl)benzene

To a solution of Intermediate 13 (2.59 g, 6.9 mmol) in toluene (50 mL)was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.55 mL, 10.3 mmol),followed by diphenyl phosphoryl azide (1.94 mL, 8.9 mmol). The reactionmixture was stirred at r.t. for 18 h. The reaction mixture was quenchedby the addition of saturated aqueous ammonium chloride solution (20 mL),then extracted with EtOAc (3×50 mL). The combined organic layers werewashed with water (30 mL), dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by flash column chromatography (SiO₂, 10-100%EtOAc/heptane), yielding the title compound (1.79 g, 79%) as a yellowsolid. δ_(H) (500 MHz, CDCl₃) 8.03-7.99 (m, 2H), 7.78-7.74 (m, 2H), 7.69(d, J 2.0 Hz, 1H), 7.55-7.52 (m, 1H), 7.46 (d, J 8.0 Hz, 1H), 4.58 (s,2H), 3.10 (s, 3H), 2.14 (s, 3H).

Intermediate 15 4-Iodo-3-methyl-6-[4-(methylsulfonyl)phenyl]isoquinoline

To a cooled (−78° C.) solution of Barluenga's Reagent (4.13 g, 10.8mmol) in DCM (65 mL) was added tetrafluoroboric acid diethyl ethercomplex (2.93 mL, 10.8 mmol). The resultant solution was added slowly toa cooled (−78° C.) solution of Intermediate 14 (1.79 g, 5.4 mmol) in DCM(5 mL) and the reaction mixture was stirred at −78° C. for 1 h. Thereaction mixture was quenched with saturated aqueous sodium thiosulfatesolution (50 mL), then extracted with EtOAc (3×50 mL). The combinedorganic layers were washed with water (30 mL), dried (MgSO₄) andconcentrated in vacuo. The residue was purified by flash columnchromatography (SiO₂, 20-100% EtOAc/heptane), yielding the titlecompound (1.48 g, 64%) as a purple-brown solid. δ_(H) (500 MHz, CDCl₃)9.09 (s, 1H), 8.30 (s, 1H), 8.13-8.10 (m, 2H), 8.01 (d, J 8.5 Hz, 1H),7.95-7.92 (m, 2H), 7.83 (dd, J 8.5, 1.5 Hz, 1H), 3.13 (s, 3H), 3.03 (s,3H). LCMS (ES⁺) 424.0 (M+H)⁺, RT 1.29 minutes.

Example 1 (Method A) 4-(2-Methoxybenzyl)-2-methylquinazoline

To a solution of 4-chloro-2-methylquinazoline (100 mg, 0.56 mmol) andtetrakis-(triphenylphosphine)palladium(0) (32 mg, 0.03 mmol) in THF (7mL) was added 2-methoxybenzylzinc chloride (0.5M in THF, 2.02 mL, 1.01mmol) dropwise over 5 minutes. The reaction mixture was heated at 50° C.for 18 h, then cooled to r.t. and quenched with saturated aqueousammonium chloride solution (2 mL). The organic solvent was removed invacuo. The residue was taken up in water (30 mL) and extracted with DCM(2×30 mL). The combined organic layers were dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by flash columnchromatography (SiO₂, 0-100% EtOAc/heptane), yielding the title compound(95 mg, 64%) as a yellow solid. δ_(H) (500 MHz, CDCl₃) 8.13 (d, J 8.0Hz, 1H), 8.01-7.88 (m, 1H), 7.79 (t, J 7.5 Hz, 1H), 7.47 (t, J 7.5 Hz,1H), 7.23-7.16 (m, 1H), 7.01 (d, J 7.0 Hz, 1H), 6.90 (d, J 8.0 Hz, 1H),6.81 (t, J 7.5 Hz, 1H), 4.59 (s, 2H), 3.90 (s, 3H), 2.89 (s, 3H). LCMS(ES⁺) 265.0 (M+H)⁺, RT 1.45 minutes.

Example 2 3-(2-Methoxybenzyl)quinoline

Prepared from 3-bromoquinoline (65 μL, 0.48 mmol),tetrakis(triphenyl-phosphine)palladium(0) (28 mg, 0.02 mmol) and2-methoxybenzylzinc chloride (0.5M in THF, 1.73 mL, 0.87 mmol) in THF (7mL) by Method A to give the title compound (29 mg, 24%). δ_(H) (500 MHz,CDCl₃) 8.88 (s, 1H), 8.09 (d, J 8.5 Hz, 1H), 7.91 (s, 1H), 7.73 (d, J8.5 Hz, 1H), 7.67-7.63 (m, 1H), 7.53-7.48 (m, 1H), 7.25-7.22 (m, 1H),7.17 (dd, J 7.5, 1.5 Hz, 1H), 6.94-6.87 (m, 2H), 4.15 (s, 2H), 3.81 (s,3H). LCMS (ES⁺) 250.1 (M+H)⁺, RT 1.59 minutes.

Example 3 4-(2-Methoxybenzyl)quinazoline

Prepared from 4-chloroquinazoline (100 mg, 0.61 mmol),tetrakis(triphenyl-phosphine)palladium(0) (35 mg, 0.03 mmol) and2-methoxybenzylzinc chloride (0.5M in THF, 2.19 mL, 1.10 mmol) in THF (7mL) by Method A to give the title compound (70 mg, 44%). δ_(H) (500 MHz,CDCl₃) 9.24 (s, 1H), 8.24 (d, J 8.5 Hz, 1H), 8.03 (d, J 8.5 Hz, 1H),7.86 (ddd, J 8.5, 7.0, 1.5 Hz, 1H), 7.59 (ddd, J 8.5, 7.0, 1.0 Hz, 1H),7.22 (td, J 8.0, 2.0 Hz, 1H), 7.11 (dd, J 7.5, 1.5 Hz, 1H), 6.93-6.84(m, 2H), 4.63 (s, 2H), 3.84 (s, 3H). LCMS (ES⁺) 251.0 (M+H)⁺. RT 1.43minutes.

Example 4 2-(2-Chlorophenoxy)-3-methylquinoxaline

A mixture of 2-chloro-3-methylquinoxaline (100 mg, 0.56 mmol),2-chlorophenol (144 mg, 1.12 mmol) and potassium carbonate (929 mg, 6.72mmol) in DMSO (5.6 mL) was heated at 120° C. in a sealed tube for 18 h.The reaction mixture was partitioned between EtOAc (60 mL) and water (60mL). The organic layer was separated and the aqueous layer wasback-extracted with 10% propan-2-ol in chloroform (2×60 mL). Thecombined organic layers were dried (Na₂SO₄) and concentrated in vacuo.The residue was purified by flash column chromatography (SiO₂, 0-100%EtOAc/heptane, followed by 1-100% MeOH/EtOAc), then repurified bypreparative HPLC, yielding the title compound (37.5 mg, 24%) as anoff-white solid. δ_(H) (500 MHz, DMSO-d₆) 8.03-7.99 (m, 1H), 7.73-7.58(m, 4H), 7.56-7.45 (m, 2H), 7.44-7.35 (m, 1H), 2.80 (s, 3H). LCMS (ES⁺)271.0/273.0 (M+H)⁺, RT 1.69 minutes.

Example 5 2-[(2-Methoxyphenyl)methyl]-3-methylquinoxaline

Prepared from 2-chloro-3-methylquinoxaline (100 mg, 0.56 mmol),tetrakis-(triphenylphosphine)palladium(0) (32 mg, 0.03 mmol) and2-methoxybenzylzinc chloride (0.5M in THF, 2.02 mL, 1.01 mmol) in THF (8mL) by Method A to give the title compound (52 mg, 35%). δ_(H) (500 MHz,DMSO-d₆) 8.01-7.92 (m, 2H), 7.78-7.69 (m, 2H), 7.24 (td, J 8.0, 2.0 Hz,1H), 7.03 (d, J 7.5 Hz, 1H), 6.92 (dd, J 7.5, 2.0 Hz, 1H), 6.85 (td, J7.5, 1.0 Hz, 1H), 4.31 (s, 2H), 3.78 (s, 3H), 2.64 (s, 3H). LCMS (ES⁺)265.0 (M+H)⁺ RT 1.55 minutes.

Example 63-Methyl-6-[4-(methylsulfonyl)phenyl]-4-(1-phenylethyl)cinnoline

Prepared from Intermediate 6 (117 mg, 0.35 mmol),tetrakis(triphenylphosphine)-palladium(0) (81 mg, 0.07 mmol) and1-phenylethylzinc chloride (0.5M in THF, 1.27 mL, 0.64 mmol) in THF (10mL) by Method A to give the title compound (32 mg, 41%). δ_(H) (500 MHz,CDCl₃) 8.58 (d, J 9.5 Hz, 1H), 8.01-7.95 (m, 2H), 7.91-7.84 (m, 2H),7.51-7.45 (m, 2H), 7.38-7.34 (m, 2H), 7.31-7.28 (m, 1H), 7.25-7.23 (m,2H), 4.99 (q, J 7.0 Hz, 1H), 3.10 (s, 3H), 3.04 (s, 3H), 1.87 (d, J 7.0Hz, 3H). LCMS (ES⁺) 403.0 (M+H)⁺, RT 1.48 minutes.

Example 74-[2-(Difluoromethoxy)benzyl]-3-methyl-6-[4-(methylsulfonyl)phenyl]cinnoline

A mixture of Intermediate 6 (50 mg, 0.14 mmol) and2-{[2-(difluoromethoxy)-phenyl]methyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(64 mg, 0.21 mmol) in 1,4-dioxane (2 mL) and 2M aqueous potassiumcarbonate solution (214 μL, 0.43 mmol) was degassed for 10 minutes undera stream of nitrogen prior to the addition of Pd(dppf)Cl₂.DCM (12 mg,0.01 mmol). The reaction mixture was heated in a sealed tube at 100° C.for 24 h. After this time, the reaction had not gone to completion sofurther2-{[2-(difluoromethoxy)phenyl]methyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(64 mg, 0.21 mmol), 2M aqueous potassium carbonate solution (100 μL,0.20 mmol) and Pd(dppf)Cl₂.DCM (12 mg, 0.01 mmol) were added. Thereaction mixture was heated at 100° C. for 3 h, then diluted with water(20 mL) and extracted with EtOAc (3×25 mL). The combined organic layerswere washed with brine (30 mL), dried (Na₂SO₄) and concentrated invacuo. The residue was purified by flash column chromatography (SiO₂,0-100% EtOAc/heptane), then repurified by preparative HPLC, yielding thetitle compound (9 mg, 15%) as a pale yellow solid. δ_(H) (500 MHz,CDCl₃) 8.64 (d, J 9.0 Hz, 1H), 8.08-8.02 (m, 3H), 7.99 (dd, J 8.5, 1.7Hz, 1H), 7.79 (d, J 8.5 Hz, 2H), 7.27-7.19 (m, 2H), 7.00 (t, J 7.5 Hz,1H), 6.69 (t, J 75.0 Hz, 1H), 6.60 (d, J 8.0 Hz, 1H), 4.53 (s, 2H), 3.10(s, 3H), 2.97 (s, 3H). LCMS (ES⁺) 455.0 (M+H)⁺, RT 1.47 minutes.

Example 82-{5-[3-Methyl-4-(1-phenylethyl)cinnolin-6-yl]pyrimidin-2-yl}propan-2-ol

Prepared from Intermediate 9 (93 mg, 0.30 mmol),tetrakis(triphenylphosphine)-palladium(0) (68 mg, 0.06 mmol) and1-phenylethylzinc chloride (0.5M in THF, 1.06 mL, 0.53 mmol) in THF (10mL) by Method A to give the title compound (17 mg, 15%). δ_(H) (500 MHz,CDCl₃) 8.66 (s, 2H), 8.62 (d, J 9.0 Hz, 1H), 7.88-7.82 (m, 2H),7.38-7.35 (m, 2H), 7.32-7.29 (m, 1H), 7.24-7.22 (m, 2H), 4.99 (q, J 7.5Hz, 1H), 4.56 (s, 1H), 3.06 (s, 3H), 1.89 (d, J 7.5 Hz, 3H), 1.64 (s,6H). LCMS (ES⁺) 385.0 (M+H)⁺, RT 1.43 minutes.

Example 92-(5-{4-[2-(Difluoromethoxy)benzyl]-3-methylcinnolin-6-yl}pyrimidin-2-yl)propan-2-ol

A mixture of Intermediate 9 (80 mg, 0.25 mmol) and2-{[2-(difluoromethoxy)-phenyl]methyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(152 mg, 0.51 mmol) in 1,4-dioxane (5 mL) and 2M aqueous potassiumcarbonate solution (381 pt, 0.76 mmol) was degassed for 10 minutes undera stream of nitrogen prior to the addition of Pd(dppf)Cl₂.DCM (10 mg,0.01 mmol). The reaction mixture was heated in a sealed tube at 100° C.for 6 h. After this time, the reaction had not gone to completion sofurther2-{[2-(difluoromethoxy)phenyl]methyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(152 mg, 0.51 mmol) in 1,4-dioxane (1 mL), 2M aqueous potassiumcarbonate solution (381 pt, 0.76 mmol) and Pd(dppf)Cl₂.DCM (10 mg, 0.01mmol) were added. The reaction mixture was heated in a sealed tube at100° C. for 18 h. The reaction mixture was cooled to r.t., diluted withwater (10 mL) and brine (10 mL), then extracted with DCM (3×20 mL). Thecombined organic layers were dried (Na₂SO₄) and concentrated in vacuo.The residue was purified by flash column chromatography (SiO₂, 20-100%EtOAc/heptane), then repurified by preparative HPLC, yielding the titlecompound (24 mg, 24%) as a pale yellow solid. δ_(H) (500 MHz, CDCl₃)8.94 (s, 2H), 8.69 (d, J 9.0 Hz, 1H), 8.03 (d, J 1.5 Hz, 1H), 7.96 (dd,J 9.0, 1.5 Hz, 1H), 7.28-7.20 (m, 2H), 7.00 (t, J 7.5 Hz, 1H), 6.69 (t,J 75.0 Hz, 1H), 6.58 (d, J 7.5 Hz, 1H), 4.56 (s, 1H), 4.53 (s, 2H), 2.98(s, 3H), 1.65 (s, 6H). LCMS (ES⁺) 437.0 (M+H)⁺, RT 1.42 minutes.

Example 102-{5-[3-Methyl-4-(2-methylphenoxy)cinnolin-6-yl]pyrimidin-2-yl}propan-2-ol

A mixture of Intermediate 10 (90 mg, 0.32 mmol) and2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol(100 mg, 0.38 mmol) in 1,4-dioxane (4 mL) and 2M aqueous potassiumcarbonate solution (474 μl, 0.95 mmol) was degassed for 10 minutes undera stream of nitrogen prior to the addition of Pd(dppf)Cl₂.DCM (13 mg,0.02 mmol). The reaction mixture was heated at 100° C. in a sealed tubefor 2 h. After this time, the reaction had not gone to completion sofurther2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol(50 mg, 0.19 mmol) was added and the reaction mixture was heated at 100°C. in a sealed tube for 2 h. The reaction mixture was cooled to r.t,then diluted with water (20 mL) and extracted with EtOAc (20 mL). Theorganic layer was separated and the aqueous layer was back-extractedwith EtOAc (2×20 mL). The combined organic layers were washed with brine(20 mL), dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified by flash column chromatography (SiO₂, 0-100% EtOAc/heptane),then repurified by preparative HPLC, yielding the title compound (56 mg,46%) as a yellow solid. δ_(H) (500 MHz, CDCl₃) 8.94 (s, 2H), 8.71 (d, J9.0 Hz, 1H), 8.04 (d, J 2.0 Hz, 1H), 7.99 (dd, J 9.0, 2.0 Hz, 1H), 7.34(d, J 7.0 Hz, 1H), 7.07-6.96 (m, 2H), 6.22 (d, J 8.0 Hz, 1H), 4.55 (s,1H), 2.75 (s, 3H), 2.54 (s, 3H), 1.64 (s, 6H). LCMS (ES⁺) 387.0 (M+H)⁺,RT 1.48 minutes.

Example 114-[2-(Difluoromethoxy)benzyl]-3-methyl-6-[4-(methylsulfonyl)phenyl]isoquinoline

A mixture of Intermediate 15 (70 mg, 0.16 mmol) and2-{[2-(difluoromethoxy)-phenyl]methyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(95 mg, 0.32 mmol) in 1,4-dioxane (5 mL) and 2M aqueous potassiumcarbonate solution (238 μL, 0.48 mmol) was degassed for 10 minutes undera stream of nitrogen prior to the addition of Pd(dppf)Cl₂.DCM (6 mg,0.01 mmol). The reaction mixture was heated in a sealed tube at 100° C.for 3 h. After this time, the reaction had not gone to completion sofurther2-{[2-(difluoromethoxy)phenyl]methyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(95 mg, 0.32 mmol) was added and the mixture was stirred at 100° C. for1.5 h. To push the reaction to completion, further2-{[2-(difluoromethoxy)phenyl]methyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(95 mg, 0.32 mmol), 2M aqueous potassium carbonate solution (238 μL,0.48 mmol) and Pd(dppf)Cl₂.DCM (6 mg, 0.01 mmol) were added and themixture was stirred at 100° C. for 18 h. Further2-{[2-(difluoromethoxy)phenyl]-methyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(95 mg, 0.32 mmol), 2M aqueous potassium carbonate solution (238 μL,0.48 mmol) and Pd(dppf)Cl₂.DCM (6 mg, 0.01 mmol) were added and themixture was stirred at 100° C. for 2 h. The reaction mixture was cooledto r.t., diluted with water (10 mL) and brine (10 mL), then extractedwith DCM (3×20 mL). The combined organic layers were dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by flash columnchromatography (SiO₂, 30-100% EtOAc/heptane), then repurified bypreparative HPLC, yielding the title compound (19 mg, 29%) as anoff-white solid. δ_(H) (500 MHz, CDCl₃) 9.22 (s, 1H), 8.09 (d, J 8.5 Hz,1H), 8.04-7.98 (m, 3H), 7.78-7.74 (m, 3H), 7.24-7.18 (m, 2H), 7.00-6.95(m, 1H), 6.70 (t, J 74.0 Hz, 1H), 6.64 (d, J 7.5 Hz, 1H), 4.51 (s, 2H),3.09 (s, 3H), 2.73 (s, 3H). LCMS (ES⁺) 454.0 (M+H)⁺, RT 1.52 minutes.

Example 123-Methyl-6-[4-(methylsulfonyl)phenyl]-4-(1-phenylethyl)isoquinoline

Prepared from Intermediate 15 (200 mg, 0.47 mmol),tetrakis(triphenyl-phosphine)palladium(0) (109 mg, 0.09 mmol) and1-phenylethylzinc chloride (0.5M in THF, 1.70 mL, 0.85 mmol) in THF (10mL) by Method A to give the title compound (31 mg, 28%). δ_(H) (500 MHz,CDCl₃) 9.14 (s, 1H), 8.01 (d, J 8.5 Hz, 1H), 7.97-7.93 (m, 2H), 7.85 (s,1H), 7.65 (dd, J 8.5, 1.5 Hz, 1H), 7.44-7.41 (m, 2H), 7.36-7.32 (m, 2H),7.30-7.26 (m, 3H), 5.03 (q, J 7.0 Hz, 1H), 3.09 (s, 3H), 2.82 (s, 3H),1.86 (d, J 7.0 Hz, 3H). LCMS (ES⁺) 402.0 (M+H)⁺, RT 1.55 minutes.

The invention claimed is:
 1. A compound represented by formula (IIB), ora pharmaceutically acceptable salt thereof:

wherein V represents C—R²² or N; R²¹ represents hydroxy(C₁₋₆)alkyl orR²¹ represents (C₃₋₇)cycloalkyl, which group is optionally substitutedby one, two, or three substituents independently selected from halogen,halo(C₁₋₆)alkyl, cyano, C₁₋₆ alkyl, trifluoromethyl, hydroxy,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl,C₁₋₆ alkylsulphonyl, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, C₂₋₆alkylcarbonylamino, (C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, C₂₋₆alkoxycarbonylamino, (C₂₋₆)alkoxycarbonylamino-(C₁₋₆)alkyl, C₁₋₆ alkylsulphonylamino, (C₁₋₆)alkyl-sulphonylamino(C₁₋₆)alkyl, formyl, C₂₋₆alkylcarbonyl, carboxy, carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆alkoxycarbonyl(C₁₋₆)alkyl, aminosulphonyl, (C₁₋₆)alkylsulphoximinyl,[(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]sulphoximinyl,(C₁₋₆)alkylsulphonylaminocarbonyl, (C₂₋₆)alkylcarbonyl-aminosulphonyl,(C₁₋₆)alkoxyaminocarbonyl, tetrazolyl and hydroxyoxadiazolyl; R²²represents hydrogen, halogen or C₁₋₆ alkyl; R²³ represents hydrogen,C₁₋₆ alkyl, trifluoromethyl or C₁₋₆ alkoxy; q is zero or 1; A representsC—R² or N; G represents the residue of a six-membered heteroaromaticring selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl; Erepresents —O—, —CH₂—, or —CH(CH₃); Q represents —CH₂— or —CH₂O; Zrepresents hydrogen or methyl; R² represents hydrogen or halogen; R¹⁵represents hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy ordifluoromethoxy; and R¹⁶ represents hydrogen, halogen, cyano, C₁₋₆alkyl, trifluoromethyl, difluoromethoxy or amino.
 2. The compound asclaimed in claim 1 wherein R²¹ represents hydroxy(C₁₋₆)alkyl.
 3. Thecompound as claimed in claim 1 represented by formula (IIF), (IIG),(IIH), or (IIJ), or a pharmaceutically acceptable salt thereof:

wherein W represents C(R³²)(R³³); R³² represents hydrogen, halogen,cyano, hydroxy, hydroxy(C₁₋₆)alkyl, C₁₋₆ alkylsulphonyl, formyl,carboxy, carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆alkoxycarbonyl(C₁₋₆)alkyl, aminosulphonyl, (C₁₋₆)alkylsulphoximinyl,[(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]sulphoximinyl,(C₁₋₆)alkylsulphonylaminocarbonyl, (C₂₋₆)alkylcarbonyl-aminosulphonyl,(C₁₋₆)alkoxyaminocarbonyl, tetrazolyl or hydroxyoxadiazolyl; R³³represents hydrogen, halogen, C₁₋₆ alkyl, trifluoromethyl, hydroxy,hydroxy-(C₁₋₆)alkyl, C₁₋₆ alkoxy, amino or carboxy; R³⁴ representshydrogen, halogen, halo(C₁₋₆)alkyl, hydroxy, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ alkylsulphinyl, C₁₋₆ alkylsulphonyl, amino, C₁₋₆alkylamino, di(C₁₋₆)alkyl-amino, (C₂₋₆)alkylcarbonylamino,(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, (C₁₋₆)alkyl-sulphonylamino or(C₁₋₆)alkylsulphonylamino(C₁₋₆)alkyl; q is zero or
 1. 4. The compound asclaimed in claim 3 wherein R³⁴ represents hydrogen, fluoro or hydroxy.5. The compound as claimed in claim 1 wherein R¹⁵ representsdifluoromethoxy.
 6. A compound that is2-{5-[3-Methyl-4-(1-phenylethyl)cinnolin-6-yl]pyrimidin-2-yl}propan-2-ol,2-(5-{4-[2-(Difluoromethoxy)benzyl]-3-methylcinnolin-6-yl}pyrimidin-2-yl)propan-2-ol,or2-{5-[3-Methyl-4-(2-methylphenoxy)cinnolin-6-yl]pyrimidin-2-yl}propan-2-ol.7. A pharmaceutical composition comprising a compound of formula (IIB)as defined in claim 1 or a pharmaceutically acceptable salt thereof, inassociation with a pharmaceutically acceptable carrier.
 8. Thepharmaceutical composition as claimed in claim 7 further comprising anadditional pharmaceutically active ingredient.